2,4-Substituted imidazolidine derivatives, their preparation, their use and pharmaceutical preparations comprising them

ABSTRACT

The present invention relates to imidazolidine compounds of the formula I,                    
     The compounds of the formula I are valuable pharmaceutical active compounds, which are suitable, for example, for the therapy and prophylaxis of inflammatory disorders, for example of rheumatoid arthritis, or of allergic disorders. The compounds of the formula I are inhibitors of the adhesion and migration of leucocytes and/or antagonists of the adhesion receptor VLA-4 belonging to the integrins group. They are generally suitable for the therapy or prophylaxis of illnesses which are caused by an undesired extent of leucocyte adhesion and/or leucocyte migration or are associated therewith, or in which cell-cell or cell-matrix interactions which are based on interactions of VLA-4 receptors with their ligands play a part. The invention furthermore relates to processes for the preparation of the compounds of the formula I, their use in the therapy and prophylaxis of the disease states mentioned and pharmaceutical preparations which contain compounds of the formula I.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to imidazolidine derivatives of theformula I,

in which B, E, W, Z, R, R⁰, R², R³, e, and h have the meanings indicatedbelow. The compounds of the formula I are valuable pharmaceuticallyactive compounds, which are suitable, for example, for the therapy andprophylaxis of inflammatory disorders, for example, of rheumatoidarthritis, or of allergic disorders. The compounds of the formula I areinhibitors of the adhesion and migration of leucocytes and/or areantagonists of the integrin adhesion receptor VLA-4. They are generallysuitable for the therapy or prophylaxis of illnesses which are caused byor associated with an undesired extent of leucocyte adhesion and/orleucocyte migration, or in illnesses in which cell-cell or cell-matrixinteractions which are based on VLA-4 receptor/ligand interactions. Theinvention furthermore relates to processes for the preparation of thecompounds of the formula I, their use in the therapy and prophylaxis ofthe disease states mentioned, and pharmaceutical preparations whichcontain compounds of the formula I.

2. Description of Related Art

The integrins are a group of adhesion receptors which play an importantpart in cell—cell-binding and cell-extracellular matrix-bindingprocesses. They have an αβ-heterodimeric structure and exhibit a widecellular distribution and are highly conserved in evolution. Theintegrins include, for example, the fibrinogen receptor on platelets,which interacts especially with the RGD sequence of fibrinogen, or thevitronectin receptor on osteoclasts, which interacts especially with theRGD sequence of vitronectin or of osteopontin. The integrins are dividedinto three major groups, the β2 subfamily with the representativesLFA-1, Mac-1 and p150/95, which are responsible in particular forcell—cell interactions of the immune system, and the subfamilies β1 andβ3, whose representatives mainly mediate cell adhesion to components ofthe extracellular matrix (Ruoslahti, Annu. Rev. Biochem. 1988, 57, 375).The integrins of the β1 subfamily, also called VLA proteins (very late(activation) antigen), include at least six receptors which interactspecifically with fibronectin, collagen and/or laminin as ligands.Within the VLA family, the integrin VLA-4 (α4β1) is atypical, insofar asit is mainly restricted to lymphoid and myeloid cells where it isresponsible for cell—cell interactions with a large number of othercells. For example, VLA-4 mediates the interaction of T and Blymphocytes with the heparin II-binding fragment of human plasmafibronectin (FN). The binding of VLA-4 with the heparin II-bindingfragment of plasma fibronectin is especially based on an interactionwith an LDVP sequence. In contrast to the fibrinogen or vitronectinreceptor, VLA-4 is not a typical RGD-binding integrin (Kilger andHolzmann, J. Mol. Meth. 1995, 73, 347).

The leucocytes circulating in the blood normally exhibit only a lowaffinity for the vascular endothelial cells which line the bloodvessels. Cytokines which are released from inflamed tissue cause theactivation of endothelial cells and thus the expression of a largenumber of cell surface antigens. These include, for example, theadhesion molecules ELAM-1 (endothelial cell adhesion molecule-1; alsodesignated as E-selectin), which, inter alia, binds neutrophils, ICAM-1(intercellular adhesion molecule-1), which interacts with LFA-1(leucocyte function-associated antigen 1) on leucocytes, and VCAM-1(vascular cell adhesion molecule-1), which binds various leucocytes,inter alia lymphocytes (Osborn et al., Cell 1989, 59, 1203). VCAM-1,like ICAM-1, is a member of the immunoglobulin gene superfamily. VCAM-1(first known as INCAM-110) was identified as an adhesion molecule whichis induced on endothelial cells by inflammatory cytokines such as TNFand IL-1 and lipopolysaccharides (LPS). Elices et al. (Cell 1990, 60,577) showed that VLA-4 and VCAM-1 form a receptor-ligand pair whichmediates the adhesion of lymphocytes to activated endothelium. Thebinding of VCAM-1 to VLA-4 does not take place via an interaction ofVLA-4 with an RGD sequence; this sequence is not contained in VCAM-1(Bergelson et al., Current Biology 1995, 5, 615). VLA-4, however, alsooccurs on other leucocytes, and the adhesion of leucocytes other thanlymphocytes is also mediated via the VCAM-1/VLA-4 adhesion mechanism.VLA-4 thus represents an individual example of a β1 integrin receptorwhich, via the ligands VCAM-1 and fibronectin, plays an important partboth in cell—cell interactions and in cell-extracellular matrixinteractions.

The cytokine-induced adhesion molecules play an important part in therecruitment of leucocytes into extravascular tissue regions. Leucocytesare recruited into inflammatory tissue regions by cell adhesionmolecules which are expressed on the surface of endothelial cells andserve as ligands for leucocyte cell surface proteins or proteincomplexes (receptors) (the terms ligand and receptor can be consideredinterchangeable here.) Leucocytes from the blood must first adhere toendothelial cells before they can migrate into the synovium. SinceVCAM-1 binds to cells which carry the integrin VLA-4 (α4β1), such aseosinophils, T and B lymphocytes, monocytes or neutrophils, theVCAM-1/VLA-4 mechanism has the function of recruiting cells of this typefrom the blood stream into areas of infection and inflammatory foci(Elices et al., Cell 1990, 60, 577; Osborn, Cell 1990, 62, 3; Issekutzet al., J. Exp. Med. 1996, 183, 2175).

The VCAM-1/VLA-4 adhesion mechanism has been connected with a number ofphysiological and pathological processes. Apart from cytokine-activatedendothelium, VCAM-1 is additionally expressed, inter alia, by thefollowing cells: myoblasts, lymphoid dendritic cells and tissuemacrophages, rheumatoid synovium, cytokine-stimulated neural cells,parietal epithelial cells of the Bowman's capsule, the renal tubularepithelium, inflamed tissue during heart and kidney transplant rejectionand by intestinal tissue in graft-versus-host disease. VCAM-1 is alsoexpressed on those tissue areas of the arterial endothelium whichcorrespond to early arteriosclerotic plaques of a rabbit model.Additionally, VCAM-1 is expressed on follicular dendritic cells of humanlymph nodes and is found on stroma cells of the bone marrow, for examplein the mouse. The latter finding points to a function of VCAM-1 inB-cell development. Apart from cells of hematopoietic origin, VLA-4 isalso found, for example, on melanoma cell lines, and the VCAM-1/VLA-4adhesion mechanism is connected with the metastasis of such tumors (Riceet al., Science 1989, 246, 1303).

The main form in which VCAM-1 occurs in vivo on endothelial cells andwhich is the dominant form in vivo is designated as VCAM-7D and carriesseven immunoglobulin domains. The domains 4, 5 and 6 are similar intheir amino acid sequences to the domains 1, 2 and 3. The fourth domainis removed in a further form, consisting of six domains, designated hereas VCAM-6D, by alternative splicing. VCAM-6D can also bindVLA-4-expressing cells.

Further details on VLA-4, VCAM-1, integrins and adhesion proteins arefound, for example, in the articles by Kilger and Holzmann, J. Mol.Meth. 1995, 73, 347; Elices, Cell Adhesion in Human Disease, Wiley,Chichester 1995, p. 79; and Kuijpers, Springer Semin. Immunopathol.1995, 16, 379.

On account of the role of the VCAM-1/VLA-4 mechanism in cell adhesionprocesses, which are important, for example, in infections,inflammations or atherosclerosis, attempts have been made to intervenein these adhesion processes to control illnesses, in particular, forexample, in inflammation (Osborn et al., Cell 1989, 59,1203). A methodof doing this is the use of monoclonal antibodies which are directedagainst VLA-4. Monoclonal antibodies (mAB) of this type, which act asVLA-4 antagonists to block the interaction between VCAM-1 and VLA-4, areknown. Thus, for example, the anti-VLA-4 mAB HP2/1 and HP1/3 inhibit theadhesion of VLA-4-expressing Ramos cells (B-cell-like cells) to humanumbilical cord endothelial cells and to VCAM-1-transfected COS cells.The anti-VCAM-1 mAB 4B9 likewise inhibits the adhesion of Ramos cells,Jurkat cells (T-cell-like cells) and HL60 cells (granulocyte-like cells)to COS cells transfected expressing VCAM-6D and VCAM-7D in vitro datawith antibodies directed against the α4 subunit of VLA-4 show thatadhesion of lymphocytes to synovial endothelial cells is blocked, anadhesion which plays a part in rheumatoid arthritis (van Dinther-Janssenet al., J. Immunol. 1991, 147, 4207).

In vivo experiments have shown that an experimental autoimmuneencephalomyelitis can be inhibited by anti-α4 mAB. The migration ofleucocytes into an inflammatory focus is likewise blocked by amonoclonal antibody against the α4 chain of VLA-4. The influencing ofthe VLA-4-dependent adhesion mechanism by antibodies was alsoinvestigated in an asthma model in order to investigate the role ofVLA-4 in the recruitment of leucocytes into inflamed lung tissue (U.S.Ser. No. 07/821,768; EP-A-626 861). The administration of anti-VLA-4antibodies inhibited the late-phase reaction and airway overreaction inallergic sheep.

The VLA-4-dependent cell adhesion mechanism was also investigated in aprimate model of inflammatory bowel disease (IBD). In this model, whichcorresponds to ulcerative colitis in man, the administration ofanti-VLA-4 antibodies resulted in a significant reduction in the acuteinflammation.

Moreover, it was possible to show that VLA-4-dependent cell adhesionplays a part in the following clinical conditions including thefollowing chronic inflammatory processes: rheumatoid arthritis(Cronstein and Weismann, Arthritis Rheum. 1993, 36, 147; Elices et al.,J. Clin. Invest. 1994, 93,405), diabetes mellitus (Yang et al., Proc.Natl. Acad. Sci. USA 1993, 90, 10494), systemic lupus erythematosus(Takeuchi et al., J. Clin. Invest. 1993, 92, 3008), allergies of thedelayed type (type IV allergy) (Elices et al., Clin. Exp. Rheumatol.1993, 11, S77), multiple sclerosis (Yednock et al., Nature 1992, 356,63), malaria (Ockenhouse et al., J. Exp. Med. 1992, 176, 1183),arteriosclerosis (O'Brien et al., J. Clin. Invest. 1993, 92, 945),transplantation (Isobe et al., Transplantation Proceedings 1994, 26,867-868), various malignancies, for example melanoma (Renkonen et al.,Am. J. Pathol. 1992, 140, 763), lymphoma (Freedman et al., Blood 1992,79, 206) and others (Albelda et al., J. Cell Biol. 1991, 114, 1059).

VLA-4 blocking by suitable antagonists accordingly offers effectivetherapeutic possibilities, in particular, for example, of treatingvarious inflammatory conditions including asthma and IBD. The particularrelevance of VLA-4 antagonists for the treatment of rheumatoid arthritisin this case results, as already stated, from the fact that leucocytesfrom the blood must first adhere to endothelial cells before they canmigrate into the synovium, and that the VLA-4 receptor plays a part inthis adhesion. The fact that VCAM-1 is induced by inflammatory agents onendothelial cells (Osbom, Cell 1990, 62, 3; Stoolman, Cell 1989, 56,907), and the recruitment of various leucocytes into areas of infectionand inflammatory foci has already been discussed above. In this respect,T cells adhere to activated endothelium mainly via the LFA-1/ICAM-1 andVLA-4/VCAM-1 adhesion mechanisms (Springer, Cell 1994, 76, 301). On mostsynovial T cells, the binding capacity of VLA-4 for VCAM-1 is increasedin rheumatoid arthritis (Postigo et al., J. Clin. Invest. 1992, 89,1445). Additionally, an increased adhesion of synovial T cells tofibronectin has been observed (Laffon et al., J. Clin. Invest. 1991, 88,546; Morales-Ducret et at., J. Immunol. 1992, 149, 1424). VLA-4 isupregulated both in the course of its expression and with respect to itsfunction on T lymphocytes of the rheumatoid synovial membrane. Theblocking of the binding of VLA-4 to its physiological ligands VCAM-1 andfibronectin makes possible an effective prevention or alleviation ofarticular inflammatory processes. This is also confirmed by experimentswith the antibody HP2/1 on Lewis rats with adjuvant arthritis, in whichan effective prevention of illness has been observed (Barbadillo et al.,Springer Semin. Immunopathol. 1995, 16, 427). VLA-4 is thus an importanttherapeutic target molecule.

The abovementioned VLA-4 antibodies and the use of antibodies as VLA-4antagonists are described in the Patent Applications WO-A-93/13798,WO-A-93/15764, WO-A-94/16094, WO-A-94/17828, and WO-A-95/19790. In thePatent Applications WO-A-94/15958, WO-A-95/15973, WO-A-96/00581,WO-A-96/06108 and WO-A-96/20216, peptide compounds are described asVLA-4 antagonists. The use of antibodies and peptide compounds aspharmaceuticals, however, has some disadvantages, for example lack oforal availability, rapid degradation or immunogenicity on longer-termuse. There is thus a need for VLA-4 antagonists having improvedproperties for use in therapy and prophylaxis.

WO-A-95/14008, WO-A-94/21607, WO-A-93/18057, EP-A-449 079, EP-A-15 530505 (U.S. Pat. No. 5,389,614), EP-A-566 919 (U.S. Pat. No. 5,397,796),EP-A-580 008 (U.S. Pat. No. 5,424,293) and EP-A-584 694 (U.S. Pat. No.5,554,594) describe substituted 5-membered ring heterocycles which havean amino, amidino or guanidino function at the N-terminal end of themolecule and which exhibit platelet aggregation-inhibiting actions.EP-A-796 855 (European Patent Application 97103712.2) describes furtherheterocycles which are inhibitors of bone resorption. EP-A-842 943,EP-A-842 945 and EP-A-842 944 (German Patent Applications 19647380.2,19647381.0 and 19647382.9) describe that certain compounds from thisseries and certain further compounds surprisingly also inhibit leucocyteadhesion and are VLA-4 antagonists. However, the selected compounds ofthe formula I according to the present invention, which aredistinguished by their VLA-4 antagonism and/or their inhibitory actionon leucocyte adhesion and leucocyte migration and are the subject of thepresent invention, are not disclosed or suggested in the applicationsmentioned.

SUMMARY OF THE INVENTION

The present invention thus relates to compounds of the formula I,

in which

W is R¹—A—C(R¹³) or R¹—CH═C;

Z is oxygen or sulfur;

A is a direct bond or (C₁-C₂)-alkylene;

B is a divalent radical selected from the group of (C₁-C₆)-alkylene,(C₂-C₆)-alkenylene, phenylene, phenylene-(C₁-C₃)-alkyl,(C₁-C₃)-alkylenephenyl, where the divalent (C₁-C₆)-alkylene radical canbe unsubstituted or substituted by a radical selected from the groupconsisting of (C₁-C₈)-alkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl,(C₃-C₁₀)-cycloalkyl, (C₃-C₁₀)-cycloalkyl-(C₁-C₆)-alkyl, optionallysubstituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₆)-alkyl optionallysubstituted in the aryl radical, optionally substituted heteroaryl, andheteroaryl-(C₁-C₆)-alkyl optionally substituted in the heteroarylradical;

E is tetrazolyl, (R⁸O)₂P(O), HOS(O)₂, R⁹NHS(O)₂, or R¹⁰CO;

R is hydrogen, (C₁-C₈)-alkyl, (C₃-C₁₂)-cycloalkyl,(C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, optionally substituted (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in the aryl radical,optionally substituted heteroaryl or heteroaryl-(C₁-C₈)-alkyl optionallysubstituted in the heteroaryl radical;

R⁰ is hydrogen, (C₁-C₈)-alkyl, (C₃-C₁₂)-cycloalkyl,(C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, (C₆-C₁₂)-bicycloalkyl,(C₆-C₁₂)-bicycloalkyl-(C₁-C₈)-alkyl, (C₆-C₁₂)-tricycloalkyl,(C₆-C₁₂)-tricycloalkyl-(C₁-C₈)-alkyl, optionally substituted(C₆-C₁₄)-aryl, (C₆-C₄)-aryl-(C₁-C₈)-alkyl optionally substituted in thearyl radical, optionally substituted heteroaryl,heteroaryl-(C₁-C₈)-alkyl optionally substituted in the heteroarylradical, H—CO, (C₁-C₈)-alkyl-CO, (C₃-C₁₂)-cycloalkyl-CO,(C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl-CO, (C₆-C₁₂)-bicycloalkyl-CO,(C₆-C₁₂)-bicycloalkyl-(C₁-C₈)-alkyl-CO, (C₆-C₁₂)-tricycloalkyl-CO,(C₆-C₁₂)-tricycloalkyl-(C₁-C₈)-alkyl-CO, optionally substituted(C₆-C₁₄)-aryl-CO, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl-CO optionally substitutedin the aryl radical, optionally substituted heteroaryl-CO,heteroaryl-(C₁-C₈)-alkyl-CO optionally substituted in the heteroarylradical, (C₁-C₈)-alkyl-S(O)_(n), (C₃-C₁₂)-cycloalkyl-S(O)_(n),(C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl-S(O)_(n),(C₆-C₁₂)-bicycloalkyl-S(O)_(n),(C₆-C₁₂)-bicycloalkyl-(C₁-C₈)-alkyl-S(O)_(n),(C₆-C₁₂)-tricycloalkyl-S(O)_(n),(C₆-C₁₂)-tricycloalkyl-(C₁-C₈)-alkyl-S(O)_(n), optionally substituted(C₆-C₁₄)-aryl-S(O)_(n), (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl-S(O), optionallysubstituted in the aryl radical, optionally substituted heteroaryl-S(O),or heteroaryl-(C₁-C₈)-alkyl-S(O), optionally substituted in theheteroaryl radical, where n is 1 or 2;

R¹ is an optionally substituted radical selected from the groupconsisting of phenyl, furyl, thienyl, pyrrolyl, imidazolyl and pyridyl,where each of these radicals can also be benzo-fused;

R² is hydrogen, (C₁-C₈)-alkyl, optionally substituted (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in the aryl radicalor (C₃-C₈)-cycloalkyl;

R³ is hydrogen, (C₁-C₈)-alkyl, optionally substituted (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in the aryl radical,optionally substituted heteroaryl, heteroaryl-(C₁-C₈)-alkyl optionallysubstituted in the heteroaryl radical, (C₃-C₈)-cycloalkyl,(C₃-C₈)-cycloalkyl-(C₁-C₈)-alkyl, (C₆-C₁₂)-bicycloalkyl,(C₆-C₁₂)-bicycloalkyl-(C₁-C₈)-alkyl, (C₆-C₁₂)-tricycloalkyl,(C₆-C₁₂)-tricycloalkyl-(C₁-C₈)-alkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl,R¹¹NH, CON(CH₃)R⁴, CONHR⁴, COOR¹⁵, CON(CH₃)R¹⁵ or CONHR¹⁵;

R⁴ is hydrogen or (C₁-C₁₀)-alkyl which can optionally be monosubstitutedor polysubstituted by identical or different radicals selected from thegroup consisting of hydroxyl, (C₁-C₈)-alkoxy, R⁵, optionally substituted(C₃-C₈)-cycloalkyl, hydroxycarbonyl, aminocarbonyl, mono- ordi-((C₁-C₁₈)-alkyl)-aminocarbonyl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkoxycarbonylwhich can also be substituted in the aryl radical,(C₁-C₈)-alkoxycarbonyl, Het-CO, R⁶—CO, tetrazolyl, and trifluoromethyl;

R⁵ is optionally substituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyloptionally substituted in the aryl radical, or an optionally substitutedmonocyclic or bicyclic 5-membered to 12-membered heterocyclic ring whichcan be aromatic, partially hydrogenated or completely hydrogenated andwhich can contain one, two or three identical or different heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur;

R⁶ is the radical of a natural or unnatural amino acid, imino acid,optionally N—(C₁-C₈)-alkylated or N—((C₆-C₁₄)-aryl-(C₁-C₈)-alkylated)azaamino acid which can also be substituted in the aryl radical, or theradical of a dipeptide, and their esters and amides, where freefunctional groups can be protected by protective groups customary inpeptide chemistry;

R⁸ is hydrogen, (C₁-C₁₈)-alkyl, optionally substituted (C₆-C₁₄)-aryl or(C₆-C₁₄)-aryl-(C₁-C₈)-alkyl which can also be substituted in the arylradical;

R⁹ is hydrogen, aminocarbonyl, (C₁-C₁₈)-alkylaminocarbonyl,(C₃-C₈)-cycloalkylaminocarbonyl, optionally substituted(C₆-C₁₄)-arylaminocarbonyl, (C₁-C₁₈)-alkyl, optionally substituted(C₆-C₁₄)-aryl or (C₃-C₈)-cycloalkyl;

R¹⁰ is hydroxyl, (C₁-C₁₈)-alkoxy, (C₆-C₁₄)-aryl-(C₁-C₈)-alkoxy which canalso be substituted in the aryl radical, optionally substituted(C₆-C₁₄)-aryloxy, (C₁-C₈)-alkylcarbonyloxy-(C₁-C₆)-alkoxy,(C₆-C₁₄)-arylcarbonyloxy-(C₁-C₆)-alkoxy, amino or mono- ordi-((C₁-C₁₈)-alkyl)-amino;

R¹¹ is hydrogen, R^(12a), R^(12a)—CO, H—CO, R^(12a)—O—CO, R^(12b)—CO,R^(12b)—CS, R^(12a)—S(O)₂ or R^(12b)—S(O)₂;

R^(12a) is (C₁-C₁₈)-alkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl,(C₃-C₁₂)-cycloalkyl, (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, optionallysubstituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionallysubstituted in the aryl radical, optionally substituted heteroaryl,heteroaryl-(C₁-C₈)-alkyl optionally substituted in the heteroarylradical, or the radical R¹⁵;

R^(12b) is amino, di-((C₁-C₁₈)-alkyl)-amino or R^(12a)—NH;

R¹³ is hydrogen, (C₁-C₆)-alkyl, optionally substituted (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₆)-alkyl optionally substituted in the aryl radical,(C₃-C₈)-cycloalkyl or (C₃-C₈)-cyclo-(C₁-C₆)-alkyl;

R¹⁵ is R¹⁶—(C₁-C₆)-alkyl or R¹⁶;

R¹⁶ is a 6-membered to 24-membered bicyclic or tricyclic radical whichis saturated or partially unsaturated and which can also contain one,two, three or four identical or different heteroatoms selected from thegroup of nitrogen, oxygen and sulfur and which can also be substitutedby one or more identical or different substituents from the groupconsisting of (C₁-C₄)-alkyl and oxo;

Het is the radical of a 5-membered to 10-membered, saturated monocyclicor polycyclic heterocycle bonded via a ring nitrogen atom, which cancontain one, two, three or four identical or different additional ringheteroatoms selected from the group consisting of oxygen, nitrogen andsulfur and which can optionally be substituted on carbon atoms and onadditional ring nitrogen atoms, where substituents on additional ringnitrogen atoms can be identical or different radicals from the groupconsisting of hydrogen, R^(h), HCO, R^(h)CO and R^(h)O—CO and R^(h) is(C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkyl-(C₁-C₈)-alkyl,optionally substituted (C₆-C₁₄)-aryl or (C₆-C₁₄)-aryl-(C₁-C₈)-alkyloptionally substituted in the aryl radical;

e and h independently of one another are 0 or 1;

in any of their stereoisomeric forms and mixtures thereof in any ratios,and any of their physiologically tolerable salts.

DETAILED DESCRIPTION OF THE INVENTION

In the compounds of the invention, alkyl radicals can be straight-chainor branched. This also applies if alkyl radicals carry substituents oroccur as substituents of other radicals, for example in alkoxy radicals,alkoxycarbonyl radicals, or arylalkyl radicals. The same applies toalkylene radicals. Examples of suitable (C₁-C₁₈)-alkyl radicals aremethyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl,n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-pentadecyl, n-hexadecyl,n-heptadecyl, n-octadecyl, isopropyl, isobutyl, isopentyl, isohexyl,3-methylpentyl, neopentyl, neohexyl, 2,3,5-trimethylhexyl, sec-butyl,tert-butyl, and tert-pentyl. Preferred alkyl radicals are methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, n-hexyl, and isohexyl. Examples of alkylene radicals aremethylene, ethylene, tri-, tetra-, penta- and hexamethylene or methyleneor ethylene substituted by an alkyl radical, for example, methylenewhich is substituted by a methyl group, an ethyl group, an isopropylgroup, an isobutyl group, a tert-butyl group, an n-pentyl group, anisopentyl group or an n-hexyl group, or, for example, ethylene which canbe substituted either on one carbon atom or on the other carbon atom oralternatively on both carbon atoms.

Alkenyl radicals and alkenylene radicals as well as alkynyl radicals canalso be straight-chain or branched. Examples of alkenyl radicals arevinyl, 1-propenyl, allyl, butenyl, 3-methyl-2-butenyl, examples ofalkenylene radicals are vinylene or propenylene and examples of alkynylradicals are ethynyl, 1-propynyl, or propargyl.

Cycloalkyl radicals are, in particular, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,cyclodecyl, cycloundecyl and cyclododecyl, which, can also besubstituted, for example, by (C₁-C₄)-alkyl. Examples of substitutedcycloalkyl radicals include 4-methylcyclohexyl and2,3-dimethylcyclopentyl. Cycloalkylene radicals may be substituted inthe same way.

Bicycloalkyl radicals, tricycloalkyl radicals and the 6-membered to24-membered bicyclic and tricyclic radicals representing R¹⁶ areformally obtained by abstraction of a hydrogen atom from bicycles ortricycles. The basic bicycles and tricycles contain only carbon atoms asring members, they can thus be bicycloalkanes or tricycloalkanes, but inthe case of the radicals representing R¹⁶ they can also contain one tofour identical or different heteroatoms selected from the groupconsisting of nitrogen, oxygen and sulfur; they can thus be aza-, oxa-and thiabicyclo- and -tricycloalkanes. If heteroatoms are contained,preferably one or two heteroatoms, in particular nitrogen atoms oroxygen atoms, are contained. The heteroatoms can occupy any desiredpositions in the bicyclic or tricyclic structure; they can be located inthe bridges or, in the case of nitrogen atoms, also on the bridgeheads.Both the bicycloalkanes and tricycloalkanes and their heteroanalogs canbe completely saturated or can contain one or more double bonds;preferably they contain one or two double bonds or are, in particular,completely saturated. Both the bicycloalkanes and tricycloalkanes aswell as the heteroanalogs and both the saturated and the unsaturatedrepresentatives can be unsubstituted or can be substituted in anydesired suitable positions by one or more oxo groups and/or one or moreidentical or different (C₁-C₄)-alkyl groups, for example, methyl groupsor isopropyl groups, preferably methyl groups. The free bond of thebicyclic or tricyclic radical can be located in any desired position ofthe molecule, and the radical can thus be bonded via a bridgehead atomor an atom in a bridge. The free bond can also be located in any desiredstereochemical position, for example, in an exo position or an endoposition.

Examples of parent structures of bicyclic ring systems, from which abicyclic radical can be derived, are norbornane(═bicyclo[2.2.1]heptane), bicyclo[2.2.2]octane and bicyclo[3.2.1]octane,examples of heteroatom-containing, unsaturated or substituted ringsystems are 7-azabicyclo[2.2.1]heptane, bicyclo[2.2.2]oct-5-ene andcamphor (═1,7,7-trimethyl-2-oxobicyclo[2.2.1]heptane).

Examples of systems from which a tricyclic radical can be derived aretwistane (═tricyclo[4.4.0.0^(3,8)]decane), adamantane(═tricyclo[3.3.1.1^(3,7)]decane), noradamantane(═tricyclo[3.3.1.0^(3,7)]nonane), tricyclo[2.2.1.0^(2,6)]heptane,tricyclo[5.3.2.0^(4,9)]dodecane, tricyclo[5.4.0.0^(2,9)]undecane ortricyclo[5.5.1.0^(3,11)]tridecane.

Preferably, bicyclic or tricyclic radicals are derived from bridgedbicycles or tricycles, i.e., from systems in which rings have two ormore than two atoms in common. Additionally preferred, if not statedotherwise, are also bicyclic or tricyclic radicals having 6 to 18 ringmembers, particularly preferably those having 6 to 14 ring members, veryparticularly preferably those having 7 to 12 ring members.

Specifically particularly preferred bicyclic and tricyclic radicals arethe 2-norbornyl radical, having either the free bond in the exo positionor having the free bond in the endo position; the 2-bicyclo[3.2.1]octylradical; the adamantyl radical; both the 1-adamantyl radical and the2-adamantyl radical; the homoadamantyl radical and the noradamantylradical, for example the 3-noradamantyl radical. Additionally preferredare the 1- and the 2-adamantyl radicals.

(C₆-C₁₄)-aryl groups are, for example, phenyl, naphthyl, for example1-naphthyl and 2-naphthyl, biphenylyl, for example 2-biphenylyl,3-biphenylyl and 4-biphenylyl, anthryl or fluorenyl, (C₆-C₁₀)-arylgroups, for example 1-naphthyl, 2-naphthyl and in particular phenyl.Aryl radicals, in particular phenyl radicals, can be monosubstituted orpolysubstituted, preferably monosubstituted, disubstituted ortrisubstituted, by identical or different radicals from the groupconsisting of (C₁-C₈)-alkyl, in particular (C₁-C₄)-alkyl,(C₁-C₈)-alkoxy, in particular (C₁-C₄)-alkoxy, halogen, nitro, amino,trifluoromethyl, hydroxyl, hydroxy-(C₁-C₄)-alkyl such as, for example,hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy,ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl,(C₁-C₄)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, tetrazolyl.The same applies, for example to radicals such as arylalkyl orarylcarbonyl. Arylalkyl radicals are, in particular, benzyl and 1- and2-naphthylmethyl, 2-, 3- and 4-biphenylylmethyl and 9-fluorenylmethyl,which can also be substituted. Substituted arylalkyl radicals are, forexample, benzyl radicals and naphthylmethyl radicals substituted in thearyl moiety by one or more (C₁-C₈)-alkyl radicals, in particular(C₁-C₄)-alkyl radicals, for example 2-, 3- and 4-methylbenzyl,4-isobutylbenzyl, 4-tert-butylbenzyl, 4-octylbenzyl, 3,5-dimethylbenzyl,pentamethylbenzyl, 2-, 3-, 4-, 5-, 6-, 7- and 8-methyl-1-naphthylmethyl,1-, 3-, 4-, 5-, 6-, 7- and 8-methyl-2-naphthylmethyl, benzyl radicalsand naphthylmethyl radicals substituted in the aryl moiety by one ormore (C₁-C₈)-alkoxy radicals, in particular (C₁-C₄)-alkoxy radicals, forexample 4-methoxybenzyl, 4-neopentyloxybenzyl, 3,5-dimethoxybenzyl,3,4-methylenedioxybenzyl, 2,3,4-trimethoxybenzyl, nitrobenzyl radicals,for example 2-, 3- and 4-nitrobenzyl, halobenzyl radicals, for example2-, 3- and 4-chlorobenzyl and 2-, 3- and 4-fluorobenzyl,3,4-dichlorobenzyl, pentafluorobenzyl, trifluoromethylbenzyl radicals,for example 3- and 4-trifluoromethylbenzyl or3,5-bis(trifluoromethyl)benzyl. Substituted arylalkyl radicals, however,can also have different substituents.

In monosubstituted phenyl radicals, the substituent can be located inthe 2-, the 3- or the 4-position, the 3- and the 4-position beingpreferred. If phenyl is disubstituted, the substituents can be in the1,2-, 1,3- or 1,4-position relative to one another. Disubstituted phenylcan thus be substituted in the 2,3-position, 2,4-position, 2,5-position,the 2,6-position, 3,4-position or the 3,5-position, relative to thelinkage site. Preferably, in disubstituted phenyl radicals the twosubstituents are arranged in the 3-position and the 4-position, relativeto the linkage site. In trisubstituted phenyl radicals, the substituentscan be present, for example, in the 2,3,4-position, the 2,3,5-position,the 2,4,5-position, the 2,4,6-position, the 2,3,6-position or the3,4,5-position. The same applies to phenylene radicals, which can bepresent, for example as 1,4-phenylene or as 1,3-phenylene.

Phenylene-(C₁-C₃)-alkyl is in particular phenylenemethyl (—C₆H₄—CH₂—)and phenyleneethyl, (C₁-C₃)-alkylenephenyl in particular methylenephenyl(—CH₂—C₆H₄-). Phenylene-(C₂-C₆)-alkenyl is in particularphenyleneethenyl and phenylenepropenyl.

Heteroarys include monocyclic or polycyclic aromatic radicals having 5to 14 ring members, which contains 1, 2, 3, 4 or 5 heteroatoms as ringmembers. Examples of heteroatoms are N, O and S. If several heteroatomsare contained, these can be identical or different. Heteroaryl radicalscan also be monosubstituted or polysubstituted, preferablymonosubstituted, disubstituted or trisubstituted, by identical ordifferent radicals selected from the group consisting of (C₁-C₈)-alkyl,in particular (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, in particular(C₁-C₄)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl,hydroxy-(C₁-C₄)-alkyl such as, for example, hydroxymethyl or1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, formyl, acetyl, cyano,hydroxycarbonyl, aminocarbonyl, (C₁-C₄)-alkoxycarbonyl, phenyl, phenoxy,benzyl, benzyloxy, or tetrazolyl. Preferably heteroaryl is a monocyclicor bicyclic aromatic radical which contains 1, 2, 3 or 4, in particular1, 2 or 3, identical or different heteroatoms selected from the groupconsisting of N, O, and S and which can be substituted by 1, 2, 3 or 4,in particular 1, 2 or 3, identical or different substituents selectedfrom the group of (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, fluorine, chlorine,nitro, amino, trifluoromethyl, hydroxyl, hydroxy-(C₁-C₄)-alkyl,(C₁-C₄)-alkoxycarbonyl, phenyl, phenoxy, benzyloxy and benzyl.Particularly preferably, heteroaryl is a monocyclic or bicyclic aromaticradical having 5 to 10 ring members, in particular a 5-membered to6-membered monocyclic aromatic radical which contains 1, 2 or 3, inparticular 1 or 2, identical or different heteroatoms selected from thegroup consisting of N, O, and S and can be substituted by 1 or 2identical or different substituents selected from the group consistingof (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, phenyl, phenoxy, benzyloxy, andbenzyl.

Heterocycles representing monocyclic or bicyclic 5-membered to12-membered heterocyclic rings can be aromatic or partially orcompletely saturated. They can be unsubstituted or substituted on one ormore carbon atoms or on one or more nitrogen atoms by identical ordifferent substituents, such as is indicated for the radical heteroaryl.In particular, the heterocyclic ring can be monosubstituted orpolysubstituted on carbon atoms by identical or different radicalsselected from the group consisting of (C₁-C₈)-alkyl, for example(C₁-C₄)-alkyl, (C₁-C₈)-alkoxy, for example (C₁-C₄)-alkoxy such asmethoxy, phenyl-(C₁-C₄)-alkoxy, for example benzyloxy, hydroxyl, oxo,halogen, nitro, amino or trifluoromethyl, and/or ring nitrogen atoms inheterocyclic rings and in heteroaryl radicals can be substituted by(C₁-C₈)-alkyl, for example (C₁-C₄)-alkyl such as methyl or ethyl, or byoptionally substituted phenyl or phenyl-(C₁-C₄)-alkyl, for example,benzyl.

Examples of heterocycles on which the heteroaryl radical or the radicalof the monocyclic or bicyclic 5-membered to 12-membered heterocyclicring can be based are pyrrole, furan, thiophene, imidazole, pyrazole,oxazole, isoxazole, thiazole, isothiazole, tetrazole, pyridine,pyrazine, pyrimidine, indole, isoindole, indazole, phthalazine,quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline,β-carboline or benzo-fused, cyclopenta-fused, cyclohexa-fused orcyclohepta-fused derivatives of these heterocycles.

Nitrogen heterocycles can also be present as N-oxides.

Radicals which can be heteroaryl or the radical of a monocyclic orbicyclic 5-membered to 12-membered heterocyclic ring are, for example,2- or 3-pyrrolyl, phenylpyrrolyl, for example 4- or 5-phenyl-2-pyrrolyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 4-imidazolyl, methylimidazolyl,for example 1-methyl-2-, -4- or -5-imidazolyl, 1,3-thiazol-2-yl,2-pyridyl, 3-pyridyl, 4-pyridyl, N-oxido-2-, -3- or -4-pyridyl,2-pyrazinyl, 2-, 4- or 5-pyrimidinyl, 2-, 3- or 5-indolyl, substituted2-indolyl, for example 1-methyl-, 5-methyl-, 5-methoxy-, 5-benzyloxy-,5-chloro- or 4,5-dimethyl-2-indolyl, 1-benzyl-2- or -3-indolyl,4,5,6,7-tetrahydro-2-indolyl, cyclohepta[b]-5-pyrrolyl, 2-, 3- or4-quinolyl, 1-, 3- or 4-isoquinolyl, 1-oxo-1,2-dihydro-3-isoquinolyl,2-quinoxalinyl, 2-benzofuranyl, 2-benzothienyl, 2-benzoxazolyl or2-benzothiazolyl or, as radicals of partially hydrogenated or completelyhydrogenated heterocyclic rings, for example also dihydropyridinyl,pyrrolidinyl, for example 2- or 3-(N-methylpyrrolidinyl), piperazinyl,morpholinyl, thiomorpholinyl, tetrahydrothienyl, benzodioxolanyl.

Heterocyclic radicals representing the radical Het can be unsubstitutedon carbon atoms and/or ring nitrogen atoms or monosubstituted orpolysubstituted, for example disubstituted, trisubstituted,tetrasubstituted or pentasubstituted, by identical or differentsubstituents. Carbon atoms can be substituted, for example, by(C₁-C₈)-alkyl, in particular (C₁-C₄)-alkyl, (C₁-C₈)-alkoxy, inparticular (C₁-C₄)-alkoxy, halogen, nitro, amino, trifluoromethyl,hydroxyl, oxo, cyano, hydroxycarbonyl, aminocarbonyl,(C₁-C₄)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, tetrazolyl,in particular by (C₁-C₄)-alkyl, for example methyl, ethyl or tert-butyl,(C₁-C₄)-alkoxy, for example methoxy, hydroxyl, oxo, phenyl, phenoxy,benzyl, benzyloxy. Sulfur atoms can be oxidized to the sulfoxide or tothe sulfone. Examples of the radical Het are 1-pyrrolidinyl,1-piperidinyl, 1-piperazinyl, 4-substituted 1-piperazinyl,4-morpholinyl, 4-thiomorpholinyl, 1-oxo-4-thiomorpholinyl,1,1-dioxo-4-thiomorpholinyl, perhydroazepin-1-yl,2,6-dimethyl-1-piperidinyl, 3,3-dimethyl-4-morpholinyl,4-isopropyl-2,2,6,6-tetramethyl-1-piperazinyl, 4-acetyl-1-piperazinyl,and 4-ethoxycarbonyl-1-piperazinyl.

The heteroaromatic radicals furyl, thienyl, pyrrolyl, imidazolyl andpyridyl representing R¹ can be bonded via any of the carbon atoms, thusthe radicals 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl,3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-pyridyl,3-pyridyl and 4-pyridyl can be present. The phenyl radical representingR¹ and the heteroaromatic radicals can also be benzo-fused, R¹ can thusalso be naphthyl, benzo[b]furyl (═benzofuryl), benzo[c]furyl,benzo[b]thienyl (═benzothienyl), benzo[c]thienyl, indolyl,benzimidazolyl, quinolyl and isoquinolyl, in particular naphthyl,benzofuryl, benzothienyl, indolyl, benzimidazolyl, quinolyl andisoquinolyl. The benzo-fused radicals representing R¹ are preferablybonded via a carbon atom in the heterocyclic ring, where they can bebonded in turn via each of these carbon atoms. Examples of suchbenzo-fused radicals representing R¹ are 1-naphthyl, 2-naphthyl,2-benzofuryl, 3-benzofuryl, 2-benzothienyl, 3-benzothienyl, 2-indolyl,3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 2-benzimidazolyl,2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl or4-isoquinolyl.

The radicals representing R¹ can be unsubstituted or can be substitutedin any desired positions by one or more, for example one, two, three orfour, identical or different substituents. The above explanations, forexample with respect to the substituent positions in phenyl radicals andheterocyclic radicals, correspondingly also apply to the radicalsrepresenting R¹. Suitable substituents on carbon atoms are thus, forexample, (C₁-C₈)-alkyl, in particular (C₁-C₄)-alkyl, (C₁-C₈)-alkoxy, inparticular (C₁-C₄)-alkoxy, halogen, nitro, amino, trifluoromethyl,hydroxyl, hydroxy-(C₁-C₄)-alkyl such as hydroxymethyl or 1-hydroxyethylor 2-hydroxyethyl, methylenedioxy, ethylenedioxy, cyano, formyl, acetyl,hydroxycarbonyl, aminocarbonyl, (C₁-C₄)-alkoxycarbonyl, phenyl, phenoxy,benzyl, benzyloxy and tetrazolyl, where these substituents can be oncarbon atoms in the heterocyclic ring and/or on carbon atoms in a fusedbenzene ring. Nitrogen atoms in pyrrolyl radicals, imidazolyl radicalsand their benzo-fused analogs can be unsubstituted or, in particular,can be substituted, for example, by (C₁-C₈)-alkyl, for example(C₁-C₄)-alkyl such as methyl or ethyl, by optionally substituted phenylor phenyl-(C₁-C₄)-alkyl, for example benzyl, or, for example, by(C₁-C₄)-alkyl-CO.

The substituent on a substituted alkylene radical representing B can onthe one hand contain a cycle when it is a substituent selected from thegroup consisting of (C₃-C₁₀)-cycloalkyl,(C₃-C₁₀)-cycloalkyl-(C₁-C₆)-alkyl, optionally substituted (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₆)-alkyl optionally substituted in the aryl radical,optionally substituted heteroaryl and heteroaryl-(C₁-C₆) optionallysubstituted in the heteroaryl radical, and on the other hand it can beacyclic if it is a substituent from the group consisting of(C₁-C₈)-alkyl, (C₂-C₈)-alkenyl and (C₂-C₈)-alkynyl. The acyclicsubstituents can contain 2, 3, 4, 5, 6, 7 or 8 carbon atoms or, in thecase of the saturated alkyl radical, also 1 carbon atom. In the case ofthe alkenyl radicals and alkynyl radicals, the double bond or triplebond can be located in any desired position and in the case of thedouble bond can have the cis configuration or trans configuration. Asexplained above, these alkyl radicals, alkenyl radicals, and alkynylradicals can be straight-chain or branched.

Examples of substituents on the (C₁-C₆)-alkylene radical representing Bare methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl,n-octyl, isopropyl, isobutyl, isopentyl, isohexyl, sec-butyl,tert-butyl, tert-pentyl, neopentyl, neohexyl, 3-methylpentyl,2-ethylbutyl, vinyl, allyl, 1-propenyl, 2-butenyl, 3-butenyl,3-methyl-2-butenyl, ethynyl, 1-propynyl, 2-propynyl, 6-hexynyl, phenyl,benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl,4-biphenylylmethyl, cyclopropyl, cyclopropylmethyl, cyclopentyl,cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclooctylpropyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl,2-furylmethyl, 2-thienylmethyl, 3-thienylmethyl or 2-(3-indolyl)ethyl.

Halogen is fluorine, chlorine, bromine or iodine, in particular fluorineor chlorine.

The radical of an amino acid, imino acid or azaamino acid or of adipeptide is obtained from the corresponding amino acid, imino acid orazaamino acid or the dipeptide as customary in peptide chemistry byformally removing a hydrogen atom from the N-terminal amino group orfrom the imino group. By means of the free bond on the amino group orthe imino group thus formed this group is then linked in peptide fashionthrough an amide bond to the CO group in the group R⁶—CO.

The natural and unnatural amino acids can be present in allstereochemical forms, for example in the D form, the L form or in theform of a mixture of stereoisomers, for example in the form of aracemate. Preferred amino acids are α-amino acids and β-amino acids;α-amino acids are particularly preferred. Suitable amino acids which maybe mentioned, for example, are (cf. Houben-Weyl, Methoden derorganischen Chemie [Methods of Organic Chemistry], Volume 15/1 and 15/2,Georg Thieme Verlag, Stuttgart, 1974):

Aad, Abu, γAbu, ABz, 2ABz, εAca, Ach, Acp, Adpd, Ahb, Aib, βAib, Ala,βAla, ΔAla, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze,Azi, Bai, Bph, Can, Cit, Cys, (Cys)₂, Cyta, Daad, Dab, Dadd, Dap, Dapm,Dasu, Djen, Dpa, Dtc, Fel, Gln, Glu, Gly, Guv, hAla, hArg, hCys, hGln,hGlu, His, hlle, hLeu, hLys, hMet, hPhe, hPro, hSer, hThr, hTrp, hTyr,Hyl, Hyp, 3Hyp, Ile, Ise, Iva, Kyn, Lant, Lcn, Leu, Lsg, Lys, βLys,ΔLys, Met, Mim, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg,Pic, Pro, ΔPro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi,βThi, Thr, Thy, Thx, Tia, Tle, Tly, Trp, Trta, Tyr, Val,tert-butylglycine (Tbg), neopentylglycine (Npg), cyclohexylglycine(Chg), cyclohexylalanine (Cha), 2-thienylalanine (Thia),2,2-diphenylaminoacetic acid, 2-(p-tolyl)-2-phenylaminoacetic acid, and2-(p-chlorophenyl)-aminoacetic acid.

If R⁶ is the radical of a natural or unnatural α-amino acid which is notbranched on the α-carbon atom, i.e., which carries a hydrogen atom onthe α-carbon atom, then the radical —N(R^(b))—CH(SC)—CO—L is present inwhich CO—L is the acid group of the amino acid or a derivative thereof,for example an ester group or an amide group, R^(b) is for examplehydrogen and SC is the side chain of the α-amino acid, i.e., forexample, one of the substituents which are contained in the α-positionof the abovementioned α-amino acids which are unbranched in theα-position. Examples of side chains are alkyl radicals, for example themethyl group in alanine or the isopropyl group in valine, the benzylradical in phenylalanine, the phenyl radical in phenylglycine, the4-aminobutyl radical in lysine or the hydroxy-carbonyl methyl group inaspartic acid. Apart from arrangement by chemical structure, such sidechains, and thus the amino acids, can also be arranged in groups withinthe meaning of the present invention on the basis of theirphysicochemical properties, for example lipophilic side chains can bedifferentiated from hydrophilic side chains which contain polar groups.Examples of lipophilic side chains which can be contained in amino acidsrepresenting R⁶ are alkyl radicals, arylalkyl radicals or aryl radicals.

Azaamino acids are natural or unnatural amino acids in which a CH unitis replaced by a nitrogen atom. For example, in α-amino acids thecentral structural unit

Suitable radicals of imino acids are, in particular, radicals ofheterocycles selected from the following group: pyrrolidine-2-carboxylicacid; piperidine-2-carboxylic acid;1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid;decahydroisoquinoline-3-carboxylic acid; octahydroindole-2-carboxylicacid; decahydroquinoline-2-carboxylic acid;octahydrocyclopenta[b]pyrrole-2-carboxylic acid;2-azabicyclo[2.2.2]octane-3-carboxylic acid;2-azabicyclo[2.2.1]heptane-3-carboxylic acid;2-azabicyclo[3.1.0]hexane-3-carboxylic acid;2-azaspiro[4.4]nonane-3-carboxylic acid;2-azaspiro[4.5]decane-3-carboxylic acid;spiro(bicyclo[2.2.1]heptane)-2,3-pyrrolidine-5-carboxylic acid;spiro(bicyclo[2.2.2]octane)-2,3-pyrrolidine-5-carboxylic acid;2-azatricyclo[4.3.0.1^(6,9)]decane-3-carboxylic acid;decahydrocyclohepta[b]pyrrole-2-carboxylic acid;decahydrocycloocta[c]pyrrole-2-carboxylic acid;octahydrocyclopenta[c]pyrrole-2-carboxylic acid;octahydroisoindole-1-carboxylic acid;2,3,3a,4,6a-hexahydrocyclopenta[b]pyrrole-2-carboxylic acid;2,3,3a,4,5,7a-hexahydroindole-2-carboxylic acid;tetrahydrothiazole-4-carboxylic acid; isoxazolidine-3-carboxylic acid;pyrazolidine-3-carboxylic acid, and hydroxypyrrolidine-2-carboxylicacid, all of which can optionally be substituted (see followingformulae):

The heterocycles on which the radicals mentioned above are based aredisclosed, for example, in U.S. Pat. No. 4,344,949; U.S. Pat. No.4,374,847; U.S. Pat. No. 4,350,704; EP-A 29,488; EP-A 31,741; EP-A46,953; EP-A 49,605; EP-A 49,658; EP-A 50,800; EP-A 51,020; EP-A 52,870;EP-A 79,022; EP-A 84,164; EP-A 89,637; EP-A 90,341; EP-A 90,362; EP-A105,102; EP-A 109,020; EP-A 111,873; EP-A271,865; and EP-A 344,682.

Dipeptides can contain natural or unnatural amino acids, imino acids andazaamino acids as structural units. In addition, the natural orunnatural amino acids, imino acids, azaamino acids and dipeptides canalso be present in the form of derivatives of the carboxylic acid group,for example as esters or amides, such as, for example, as methyl esters,ethyl esters, n-propyl esters, isopropyl esters, isobutyl esters,tert-butyl esters, benzyl esters, unsubstituted amides, methylamides,ethylamides, semicarbazides or ω-amino-(C₂-C₈)-alkylamides.

Functional groups in radicals of amino acids, imino acids, azaaminoacids and dipeptides as well as in other parts of the molecules of theformula I can be present in protected form. Suitable protective groupssuch as, for example, urethane protective groups, carboxyl protectivegroups and side chain protective groups are described in Hubbuch,Kontakte (Merck) 1979, No. 3, pages 14 to 23, and in Büllesbach,Kontakte (Merck) 1980, No. 1, pages 23 to 35. The following may bementioned in particular: Aloc, Pyoc, Fmoc, Tcboc, Z, Boc, Ddz, Bpoc,Adoc, Msc, Moc, Z(NO₂), Z(Hal_(n)), Bobz, Iboc, Adpoc, Mboc, Acm,tert-butyl, OBzl, ONbzl, OMbzl, Bzl, Mob, Pic, Trt.

Physiologically tolerable salts of the compounds of the formula I are inparticular pharmaceutically utilizable or nontoxic salts. In the case ofcompounds of the formula I which contain acidic groups, for examplecarboxylic acid groups, such salts are, for example, alkali metal saltsor alkaline earth metal salts as well as salts with ammonia andphysiologically tolerable organic amines. Such compounds of the formulaI can thus be present, for example, as sodium salts, potassium salts,calcium salts, magnesium salts or as acid addition salts with aminessuch as, for example, triethylamine, ethanolamine,tris(2-hydroxyethyl)amine or amino acids, in particular basic aminoacids.

Compounds of the formula I which contain basic groups, for example anamino group or a guanidino group, form salts with inorganic acids, suchas, for example, hydrochloric acid, sulfuric acid or phosphoric acid,and with organic carboxylic acids or sulfonic acids, such as, forexample, acetic acid, citric acid, benzoic acid, maleic acid, fumaricacid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid. Ifthe compounds of the formula I simultaneously contain acidic and basicgroups in the molecule, the invention also includes internal salts orbetaines in addition to the salt forms described.

Salts can be obtained from the compounds of the formula I according tocustomary procedures known to the person skilled in the art, for exampleby combining with an organic or inorganic acid or base in a solvent ordispersant, or alternatively from other salts by anion exchange orcation exchange. The present invention also includes all salts of thecompounds of the formula I which are not directly suitable for use inpharmaceuticals because of low physiological tolerability, but aresuitable, for example, as intermediates for chemical reactions or forthe preparation of physiologically tolerable salts.

The compounds of the formula I can be present in stereoisomeric forms.If the compounds of the formula I contain one or more centers ofasymmetry, these can independently of one another have the Sconfiguration or the R configuration. The invention includes allpossible stereoisomers, for example enantiomers and diastereomers, andmixtures of two or more stereoisomeric forms, for example mixtures ofenantiomers and/or diastereomers, in all ratios. The invention thusrelates to enantiomers in enantiomerically pure form, both aslevorotatory and dextrorotatory antipodes, in the form of racemates andin the form of mixtures of the two enantiomers in all ratios. In thepresence of cis/trans isomerism, the invention relates to both the cisform and the trans form and mixtures of these forms. Individualstereoisomers can be prepared, if desired, by separation of a mixtureaccording to customary methods, for example by chromatography orcrystallization, by use of stereochemically homogeneous startingsubstances in the synthesis or by stereoselective synthesis. Ifappropriate, derivatization can be carried out before separation ofstereoisomers. A stereoisomer mixture can be separated at the stage ofthe compounds of the formula I or at the stage of a starting substanceor of an intermediate in the course of the synthesis. The compounds ofthe formula I according to the invention can moreover contain mobilehydrogen atoms, i.e., be present in various tautomeric forms. Thepresent invention also relates to all these tautomers. The presentinvention furthermore includes all solvates of compounds of the formulaI, for example hydrates or adducts with alcohols, as well as derivativesof the compounds of the formula I, for example esters, prodrugs andactive metabolites.

The individual structural elements in the formula I preferablyindependently of one another have the following meanings.

W is preferably R¹—A—C(R¹³).

Z is preferably oxygen.

A is preferably a direct bond or methylene, particularly preferably adirect bond.

B is preferably a divalent radical selected from the group consisting ofmethylene, ethylene, trimethylene, tetramethylene, vinylene, phenyleneor a substituted (C₁-C₄)-alkylene radical. Particularly preferably, B isa divalent methylene radical or ethylene radical (═1,2-ethylene), inparticular a methylene radical, where each of these radicals can beunsubstituted or substituted. Very particularly preferably, B is asubstituted methylene radical or ethylene radical, in particular asubstituted methylene radical. If a divalent alkylene radicalrepresenting B, in particular a methylene radical or ethylene radical(═1,2-ethylene), is substituted, it is preferably substituted by aradical selected from the group consisting of (C₁-C₈)-alkyl,(C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl, (C₃-C₇)-cycloalkyl, in particular(C₅-C₆)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, in particular(C₅-C₆)-cycloalkyl-(C₁-C₄)-alkyl, optionally substituted (C₆-C₁₀)-aryl,(C₆-C₁₀)-aryl-(C₁-C₄)-alkyl optionally substituted in the aryl radical,optionally substituted heteroaryl and heteroaryl-(C₁-C₄)-alkyloptionally substituted in the heteroaryl radical. Particularlypreferably, a substituted alkylene radical representing B is substitutedby (C₁-C₈)-alkyl, i.e., by a straight-chain or branched alkyl radicalhaving 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.

E is preferably tetrazolyl or R¹⁰CO, particularly preferably R¹⁰CO.

R is preferably hydrogen, (C₁-C₈)-alkyl or benzyl, particularlypreferably hydrogen or (C₁-C₈)-alkyl, very particularly preferablyhydrogen or (C₁-C₄)-alkyl, in particular hydrogen, methyl or ethyl.

R⁰ is preferably (C₁-C₈)-alkyl, (C₃-C₁₂)-cycloalkyl,(C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, (C₆-C₁₂)-bicycloalkyl,(C₆-C₁₂)-bicycloalkyl-(C₁-C₈)-alkyl, (C₆-C₁₂)-tricycloalkyl,(C₆-C₁₂)-tricycloalkyl-(C₁-C₈)-alkyl, optionally substituted(C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in thearyl radical, optionally substituted heteroaryl orheteroaryl-(C₁-C₈)-alkyl optionally substituted in the heteroarylradical, particularly preferably (C₁-C₈)-alkyl, (C₃-C₁₂)-cycloalkyl,(C₃-C₁₂)-cycloalkyl-(C₁-C₄)-alkyl, optionally substituted (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₄)-alkyl optionally substituted in the aryl radical,optionally substituted heteroaryl or heteroaryl-(C₁-C₄)-alkyl optionallysubstituted in the heteroaryl radical, very particularly preferablyoptionally substituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₄)-alkyloptionally substituted in the aryl radical, optionally substitutedheteroaryl or heteroaryl-(C₁-C₄)-alkyl optionally substituted in theheteroaryl radical, moreover preferably (C₆-C₁₄)-aryl-(C₁-C₄)-alkyloptionally substituted in the aryl radical or heteroaryl-(C₁-C₄)-alkylsubstituted in the heteroaryl radical. It is especially preferred if R⁰is (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl optionally substituted in the arylradical, in particular biphenylylmethyl, naphthylmethyl or benzyl whichis unsubstituted or monosubstituted or polysubstituted in the arylradical.

R¹ is preferably a radical selected from the group consisting of phenyl,furyl, thienyl, pyrrolyl, imidazolyl and pyridyl, which is notbenzo-fused. Particularly preferably, R¹ is a phenyl radical, a 2-furylradical, a 3-furyl radical, a 2-thienyl radical, a 3-thienyl radical, a3-pyrrolyl radical, a 4-imidazolyl radical, a 3-pyridyl radical or a4-pyridyl radical, very particularly preferably a phenyl radical, a2-furyl radical, a 3-furyl radical, a 2-thienyl radical, a 3-thienylradical, a 4-imidazolyl radical or a 4-pyridyl radical, moreoverpreferably a phenyl radical or a 4-pyridyl radical. Preferably, aradical representing R¹ is unsubstituted or substituted by one, two orthree, in particular by one or by two, identical or different radicalsof the type which are indicated above as suitable substituents on carbonatoms and nitrogen atoms in R¹. Particularly preferably, a radicalrepresenting R¹ is unsubstituted. Preferred substituents on carbon atomsin the radical R¹ are (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, halogen, amino,trifluoromethyl, hydroxyl, hydroxy-(C₁-C₄)-alkyl, methylenedioxy,ethylenedioxy, phenyl, phenoxy, benzyl and benzyloxy, in particular assubstituents on carbon atoms of a heteroaryl radical representing R¹.Particularly preferred substituents on carbon atoms in R¹, in particularon carbon atoms of a phenyl radical representing R¹, are (C₁-C₄)-alkyl,(C₁-C₄)-alkoxy, halogen, trifluoromethyl, hydroxyl,hydroxy-(C₁-C₄)-alkyl, methylenedioxy, ethylenedioxy, phenyl, phenoxy,benzyl and benzyloxy.

R² is preferably hydrogen or (C₁-C₈)-alkyl, particularly preferablyhydrogen or (C₁-C₄)-alkyl.

R³ is preferably (C₁-C₈)-alkyl, optionally substituted (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₄)-alkyl optionally substituted in the aryl radical,(C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkyl-(C₁-C₄)-alkyl,(C₆-C₁₂)-bicycloalkyl, (C₆-C₁₂)-bicycloalkyl-(C₁-C₄)-alkyl,(C₆-C₁₂)-tricycloalkyl, (C₆-C₁₂)-tricycloalkyl-(C₁-C₄)-alkyl,(C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl, optionally substituted heteroaryl,heteroaryl-(C₁-C₄)-alkyl optionally substituted in the heteroarylradical, R¹¹NH, CON(CH₃)R⁴, CONHR⁴, CON(CH₃)R¹⁵ or CONHR¹⁵, particularlypreferably optionally substituted (C₆-C₁₄)-aryl, in particularoptionally substituted (C₆-C₁₀)-aryl, optionally substituted 5-memberedor 6-membered heteroaryl having one or two identical or differentheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur, in particular pyridyl, R¹¹NH, CON(CH₃)R⁴, CONHR⁴, CON(CH₃)R¹⁵ orCONHR¹⁵, very particularly preferably optionally substituted(C₆-C₁₀)-aryl, R¹¹NH, CON(CH₃)R⁴, CONHR⁴, CON(CH₃)R¹⁵ or CONHR¹⁵.

R⁴ is preferably (C₁-C₈)-alkyl which can optionally be substituted asindicated above in the definition of R⁴, particularly preferably(C₁-C₈)-alkyl, in particular (C₁-C₆)-alkyl, which is substituted by oneor two of the substituents indicated in the above definition of R⁴. Itis very particularly preferred if one of the substituents is bonded inthe 1-position of the alkyl group, i.e., to that carbon atom of thealkyl group to which the nitrogen atom in the group CONHR⁴ or in thegroup CON(CH₃)R⁴ is also bonded, and if this substituent in the1-position is one of the radicals hydroxycarbonyl, aminocarbonyl, mono-or di-((C₁-C₁₈)-alkyl)-aminocarbonyl,(C₆-C₁₄)-aryl-(C₁-C₈)-alkoxycarbonyl which can also be substituted inthe aryl radical, Het-CO, R⁶—CO, (C₁-C₈)-alkoxycarbonyl or tetrazolyl.In this very particularly preferred case, the radical —NHR⁴ or theradical —N(CH₃)R⁴ is thus the radical of an α-amino acid or of anN-methyl-α-amino acid or of a derivative thereof, where this radical isformally obtained by abstraction of a hydrogen atom from the amino groupof the amino acid. Especially preferred α-amino acids are in this casethose having a lipophilic side chain, for example phenylglycine,phenylalanine, valine, leucine, isoleucine and homologs thereof, as wellas derivatives of these amino acids such as esters, amides or thederivatives in which the carboxylic acid group is converted into theradical Het-CO.

R¹¹ is preferably hydrogen, R^(12a), R^(12a)—CO, H—CO, R^(12a)—O—CO,R^(12b)—CO, R^(12b)CS or R^(12a)—S(O)₂, particularly preferablyhydrogen, R^(12a), R^(12a)—CO, R^(12a)—O—CO, R^(12b)—CO, R^(12b)—CS orR^(12a)—S(O)₂, very particularly preferably R^(12a), R^(12a)—CO,R^(12a)—O—CO, R^(12b)—CO, R^(12b)—CS or R^(12a)—S(O)₂, moreoverpreferably R^(12a), R^(12a)CO, R^(12a)—O—CO, R^(12b)—CO orR^(12a)—S(O)₂.

R^(12a) is preferably (C₁-C₁₀)-alkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl,(C₃-C₁₂)-cycloalkyl, (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, optionallysubstituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionallysubstituted in the aryl radical, optionally substituted heteroaryl,heteroaryl-(C₁-C₈)-alkyl optionally substituted in the heteroarylradical, or the radical R¹⁵.

R^(12b) is preferably R^(12a)—NH.

R¹³ is preferably hydrogen, (C₁-C₆)-alkyl, (C₃-C₈)-cycloalkyl or benzyl,particularly preferably hydrogen or (C₁-C₆)-alkyl, very particularlypreferably hydrogen or (C₁-C₄)-alkyl, in particular (C₁-C₄)-alkyl, wherea preferred alkyl radical representing R¹³ is the methyl radical.

R¹⁵ is preferably R¹⁶—(C₁-C₃)-alkyl or R¹⁶, particularly preferablyR¹⁶—(C₁)-alkyl or R¹⁶. Additionally preferably, R¹⁵, if R³ is COOR¹⁵, isthe exo-2-norbornyl radical, the endo-2-norbornyl radical or thebicyclo[3.2.1]octyl radical, and R¹⁵, if R³ is CONHR¹⁵, is theexo-2-norbomyl radical, the endo-2-norbornyl radical, the 3-noradamantylradical and in particular the 1-adamantyl radical, the 2-adamantylradical, the 1-adamantylmethyl radical or the 2-adamantylmethyl radical.

R¹⁶ is preferably a 6-membered to 14-membered, in particular 7-memberedto 12-membered, bridged bicyclic or tricyclic radical which is saturatedor partially unsaturated and which can also contain one to four, inparticular one, two or three, especially one or two, identical ordifferent heteroatoms selected from the group consisting of nitrogen,oxygen and sulfur and which can also be substituted by one or moreidentical or different substituents selected from the group consistingof (C₁-C₄)-alkyl and oxo.

Het is preferably the radical of a 5-membered to 10-membered, saturatedmonocyclic or polycyclic heterocycle bonded via a ring nitrogen atom,which can contain one or two identical or different additional ringheteroatoms selected from the group consisting of oxygen, nitrogen andsulfur and can be optionally substituted on carbon atoms and on ringnitrogen atoms, where substituents on additional ring nitrogen atoms canbe identical or different radicals selected from the group consisting ofhydrogen, R^(h), HCO, R^(h)CO or R^(h)O—CO. Particularly preferably, Hetis a heterocycle of this type which contains no additional ringheteroatom or which contains one additional ring heteroatom selectedfrom the group consisting of nitrogen, oxygen and sulfur, veryparticularly preferably Het is the radical of a 5-membered, 6-memberedor 7-membered, saturated monocyclic heterocycle bonded via a nitrogenatom, which contains no additional ring heteroatom or which contains oneadditional ring heteroatom from the group consisting of nitrogen, oxygenand sulfur, where also in these cases the radical Het can beunsubstituted or can be substituted on carbon atoms and/or on additionalring nitrogen atoms.

If R³ is one of the radicals (C₁-C₈)-alkyl, optionally substituted(C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in thearyl radical, optionally substituted heteroaryl,heteroaryl-(C₁-C₈)-alkyl optionally substituted in the heteroarylradical, (C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkyl-(C₁-C₈)-alkyl,(C₆-C₁₂)-bicycloalkyl, (C₆-C₁₂)-bicycloalkyl-(C₁-C₈)-alkyl,(C₆-C₁₂)-tricycloalkyl, (C₆-C₁₂)-tricycloalkyl-(C₁-C₈)-alkyl,(C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl, CON(CH₃)R⁴, CONHR⁴, COOR¹⁵,CON(CH₃)R¹⁵ or CONHR¹⁵, e is preferably 0 and h is preferably 1. If R³is R¹¹NH, e is preferably 1 and h is preferably 0.

Preferred compounds of the formula I are those compounds in which one ormore of the radicals have preferred meanings, all combinations ofpreferred substituent meanings being a subject of the present invention.Particularly preferred compounds of the formula I are those in which,simultaneously

W is R¹—A—C(R¹³);

Z is oxygen or sulfur;

A is a direct bond or methylene;

B is a divalent methylene radical or ethylene radical, both of which canbe unsubstituted or can be substituted by a radical selected from thegroup consisting of (C₁-C₈)-alkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl,(C₃-C₁₀)-cycloalkyl, (C₃-C₁₀)-cycloalkyl-(C₁-C₆)-alkyl, optionallysubstituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₆)-alkyl optionallysubstituted in the aryl radical, optionally substituted heteroaryl andheteroaryl-(C₁-C₆)-alkyl optionally substituted in the heteroarylradical;

E is tetrazolyl or R¹⁰CO;

R is hydrogen or (C₁-C₈)-alkyl;

R⁰ is hydrogen, (C₁-C₈)-alkyl, (C₃-C₁₂)-cycloalkyl,(C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, (C₆-C₁₂)-bicycloalkyl,(C₆-C₁₂)-bicycloalkyl-(C₁-C₈)-alkyl, (C₆-C₁₂)-tricycloalkyl,(C₆-C₁₂)-tricycloalkyl-(C₁-C₈)-alkyl, optionally substituted(C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in thearyl radical, optionally substituted heteroaryl,heteroaryl-(C₁-C₈)-alkyl optionally substituted in the heteroarylradical, H—CO, (C₁-C₈)-alkyl-CO, (C₃-C₁₂)-cycloalkyl-CO,(C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl-CO, (C₆-C₁₂)-bicycloalkyl-CO,(C₆-C₁₂)-bicycloalkyl-(C₁-C₈)-alkyl-CO, (C₆-C₁₂)-tricycloalkyl-CO,(C₆-C₁₂)-tricycloalkyl-(C₁-C₈)-alkyl-CO, optionally substituted(C₆-C₁₄)-aryl-CO, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl-CO optionally substitutedin the aryl radical, optionally substituted heteroaryl-CO,heteroaryl-(C₁-C₈)-alkyl-CO optionally substituted in the heteroarylradical, (C₁-C₈)-alkyl-S(O)_(n), (C₃-C₁₂)-cycloalkyl-S(O)_(n),(C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl-S(O)_(n),(C₆-C₁₂)-bicycloalkyl-S(O)_(n),(C₆-C₁₂)-tricycloalkyl-(C₁-C₈)-alkyl-S(O)_(n), optionally substituted(C₈-C₁₄)-aryl-S(O)_(n), (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl-S(O)_(n) optionallysubstituted in the aryl radical, optionally substitutedheteroaryl-S(O)_(n) or heteroaryl-(C₁-C₈)-alkyl-S(O)_(n) optionallysubstituted in the heteroaryl radical, where n is 1 or 2;

R¹ is an optionally substituted radical selected from the group ofphenyl, furyl, thienyl, pyrrolyl, imidazolyl and pyridyl, where each ofthese radicals can also be benzo-fused;

R² is hydrogen or (C₁-C₈)-alkyl;

R³ is hydrogen, (C₁-C₈)-alkyl, optionally substituted (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in the aryl radical,optionally substituted heteroaryl, heteroaryl-(C₁-C₈)-alkyl optionallysubstituted in the heteroaryl radical, (C₃-C₈)-cycloalkyl,(C₃-C₈)-cycloalkyl-(C₁-C₈)-alkyl, (C₆-C₁₂)-bicycloalkyl,(C₆-C₁₂)-bicycloalkyl-(C₁-C₈)-alkyl, (C₆-C₁₂)-tricycloalkyl,(C₆-C₁₂)-tricycloalkyl-(C₁-C₈)-alkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl,R¹¹NH, CON(CH₃)R⁴, CONHR⁴, COOR¹⁵, CON(CH₃)R¹⁵ or CONHR¹⁵;

R⁴ is (C₁-C₈)-alkyl which can optionally be monosubstituted orpolysubstituted by identical or different radicals selected from thegroup consisting of hydroxyl, (C₁-C₈)-alkoxy, R⁵, optionally substituted(C₃-C₈)-cycloalkyl, hydroxycarbonyl, aminocarbonyl, mono- ordi-((C₁-C₁₈)-alkyl)-aminocarbonyl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkoxycarbonyl,which can also be substituted in the aryl radical,(C₁-C₈)-alkoxycarbonyl, Het-CO, R⁶—CO, tetrazolyl and trifluoromethyl;

R⁵ is optionally substituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyloptionally substituted in the aryl radical or an optionally substitutedmonocyclic or bicyclic 5-membered to 12-membered heterocyclic ring,which can be aromatic, partially hydrogenated or completely hydrogenatedand which can contain one, two or three identical or differentheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur;

R⁶ is the radical of a natural or unnatural amino acid, imino acid,optionally N—(C₁-C₈)-alkylated or N—((C₆-C₁₄)-aryl-(C₁-C₈)-alkylated)azaamino acid which can also be substituted in the aryl radical, or theradical of a dipeptide, as well as their esters and amides, where freefunctional groups can be protected by protective groups customary inpeptide chemistry;

R¹⁰ is hydroxyl, (C₁-C₁₈)-alkoxy, (C₆-C₁₄)-aryl-(C₁-C₈)-alkoxy which canalso be substituted in the aryl radical, optionally substituted(C₆-C₁₄)-aryloxy, (C₁-C₈)-alkylcarbonyloxy-(C₁-C₆)-alkoxy,(C₆-C₁₄)-arylcarbonyloxy-(C₁-C₆)-alkoxy, amino or mono- ordi-((C₁-C₁₈)-alkyl)-amino;

R¹¹ is hydrogen, R^(12a), R^(12a)—CO, R^(12a)—O—CO, R^(12b)—CO,R^(12b)—CS or R^(12a)—S(O)₂;

R^(12a) is (C₁-C₁₈)-alkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl,(C₃-C₁₂)-cycloalkyl, (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, optionallysubstituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionallysubstituted in the aryl radical, optionally substituted heteroaryl,heteroaryl-(C₁-C₈)-alkyl optionally substituted in the heteroarylradical, or the radical R¹⁵;

R^(12b) is amino, di-((C₁-C₁₈)-alkyl)-amino or R^(12a)—NH;

R¹³ is hydrogen or (C₁-C₆)-alkyl;

R¹⁵ is R¹⁶—(C₁-C₆)-alkyl or R¹⁶;

R¹⁶ is a 6-membered to 14-membered bicyclic or tricyclic radical whichis saturated or partially unsaturated and which can also contain one,two, three or four identical or different heteroatoms selected from thegroup consisting of nitrogen, oxygen and sulfur and which can also besubstituted by one or more identical or different substituents selectedfrom the group consisting of (C₁-C₄)-alkyl and oxo;

Het is the radical of a 5-membered to 10-membered, saturated monocyclicor polycyclic heterocycle, bonded via a ring nitrogen atom, which cancontain one, two, three or four identical or different additional ringheteroatoms selected from the group of oxygen, nitrogen and sulfur andwhich can optionally be substituted on carbon atoms and on additionalring nitrogen atoms, where substituents on additional ring nitrogenatoms can be identical or different radicals selected from the group ofhydrogen, R^(h), HCO, R^(h)CO or R^(h)O—CO and R^(h) is (C₁-C₈)-alkyl,(C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkyl-(C₁-C₈)-alkyl, optionallysubstituted (C₆-C₁₄)-aryl or (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionallysubstituted in the aryl radical;

e and h independently of one another are 0 or 1;

in all their stereoisomeric forms and mixtures thereof in all ratios,and their physiologically tolerable salts.

Very particularly preferred compounds of the formula I are those inwhich, simultaneously

W is R¹—A—C(R¹³);

Z is oxygen;

A is a direct bond or methylene;

B is a divalent methylene radical or ethylene radical, both of which canbe unsubstituted or can be substituted by a radical selected from thegroup consisting of (C₁-C₈)-alkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl,(C₃-C₁₀)-cycloalkyl, (C₃-C₁₀)-cycloalkyl-(C₁-C₆)-alkyl, optionallysubstituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₆)-alkyl, optionallysubstituted in the aryl radical, optionally substituted heteroaryl andheteroaryl-(C₁-C₆)-alkyl optionally substituted in the heteroarylradical;

E is R¹⁰CO;

R is hydrogen or (C₁-C₄)-alkyl;

R⁰ is (C₁-C₈)-alkyl, (C₃-C₁₂)-cycloalkyl,(C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, (C₆-C₁₂)-bicycloalkyl,(C₆-C₁₂)-bicycloalkyl-(C₁-C₈)-alkyl, (C₆-C₁₂)-tricycloalkyl,(C₆-C₁₂)-tricycloalkyl-(C₁-C₈)-alkyl, optionally substituted(C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in thearyl radical, optionally substituted heteroaryl orheteroaryl-(C₁-C₈)-alkyl optionally substituted in the heteroarylradical;

R¹ is an optionally substituted radical selected from the groupconsisting of phenyl, furyl, thienyl, pyrrolyl, imidazolyl and pyridyl;

R² is hydrogen or (C₁-C₄)-alkyl;

R³ is (C₁-C₈)-alkyl, optionally substituted (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₄)-alkyl optionally substituted in the aryl radical,optionally substituted heteroaryl, heteroaryl-(C₁-C₄)-alkyl optionallysubstituted in the heteroaryl radical, (C₃-C₈)-cycloalkyl,(C₃-C₈)-cycloalkyl-(C₁-C₄)-alkyl, (C₆-C₁₂)-bicycloalkyl,(C₆-C₁₂)-bicycloalkyl-(C₁-C₄)-alkyl, (C₆-C₁₂)-tricycloalkyl,(C₆-C₁₂)-tricycloalkyl-(C₁-C₄)-alkyl, R¹¹NH, CON(CH₃)R⁴, CONHR⁴, COOR¹⁵,CON(CH₃)R¹⁵ or CONHR¹⁵;

R⁴ is (C₁-C₈)-alkyl which can optionally be monosubstituted orpolysubstituted by identical or different radicals from the groupconsisting of hydroxyl, (C₁-C₈)-alkoxy, R⁵, optionally substituted(C₃-C₈)-cycloalkyl, hydroxycarbonyl, aminocarbonyl, mono- ordi-((C₁-C₈)-alkyl)-aminocarbonyl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkoxycarbonylwhich can also be substituted in the aryl radical,(C₁-C₈)-alkoxycarbonyl, Het-CO, R⁶—CO, tetrazolyl and trifluoromethyl;

R⁵ is optionally substituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyloptionally substituted in the aryl radical or an optionally substitutedmonocyclic or bicyclic 5-membered to 12-membered heterocyclic ring,which can be aromatic, partially hydrogenated or completely hydrogenatedand which can contain one, two or three identical or differentheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur;

R⁶ is the radical of a natural or unnatural amino acid, imino acid oroptionally N—(C₁-C₈)-alkylated or N—((C₆-C₁₄)-aryl-(C₁-C₈)-alkylated)azaamino acid which can also be substituted in the aryl radical, as wellas their esters and amides, where free functional groups can beprotected by protective groups customary in peptide chemistry;

R¹⁰ is hydroxyl, (C₁-C₈)-alkoxy, (C₆-C₁₄)-aryl-(C₁-C₈)-alkoxy which canalso be substituted in the aryl radical, optionally substituted(C₆-C₁₄)-aryloxy, (C₁-C₈)-alkylcarbonyloxy-(C₁-C₆)-alkoxy,(C₆-C₁₄)-arylcarbonyloxy-(C₁-C₆)-alkoxy, amino or mono- ordi-((C₁-C₈)-alkyl)-amino;

R¹¹ is R^(12a), R^(12a)—CO, R^(12a)—O—CO, R^(12b)—CO or R^(12a)—S(O)₂;

R^(12a) is (C₁-C₁₀)-alkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl,(C₃-C₁₂)-cycloalkyl, (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, optionallysubstituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionallysubstituted in the aryl radical, optionally substituted heteroaryl,heteroaryl-(C₁-C₈)-alkyl optionally substituted in the heteroarylradical, or the radical R¹⁵;

R^(12b) is amino, di-((C₁-C₁₀)-alkyl)-amino or R^(12a)—NH;

R¹³ is hydrogen or (C₁-C₄)-alkyl;

R¹⁵ is R¹⁶—(C₁-C₃)-alkyl or R¹⁶;

R¹⁶ is a 7-membered to 12-membered bicyclic or tricyclic radical whichis saturated or partially unsaturated and which can also contain one ortwo identical or different heteroatoms selected from the groupconsisting of nitrogen, oxygen and sulfur and which can also besubstituted by one or more identical or different substituents selectedfrom the group consisting of (C₁-C₄)-alkyl and oxo;

Het is the radical of a 5-membered to 10-membered, saturated monocyclicor polycyclic heterocycle bonded via a ring nitrogen atom, which cancontain one or two identical or different additional ring heteroatomsselected from the group consisting of oxygen, nitrogen and sulfur andwhich can optionally be substituted on carbon atoms and additional ringnitrogen atoms, where substituents on additional ring nitrogen atoms canbe identical or different radicals selected from the group consisting ofhydrogen, R^(h), HCO, R^(h)CO or R^(h)O—CO and R^(h) is (C₁-C₆)-alkyl,(C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkyl-(C₁-C₄)-alkyl, optionallysubstituted (C₆-C₁₄)-aryl or (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl optionallysubstituted in the aryl radical;

e and h independently of one another are 0 or 1;

in all their stereoisomeric forms and mixtures thereof in all ratios,and their physiologically tolerable salts.

Additionally preferred compounds of the formula I are those in which,simultaneously

W is R¹—A—C(R¹³);

Z is oxygen;

A is a direct bond or methylene;

B is an unsubstituted methylene radical or a methylene radical which issubstituted by a radical selected from the group consisting of(C₁-C₈)-alkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, optionally substituted (C₆-C₁₀)-aryl,(C₆-C₁₀)-aryl-(C₁-C₄)-alkyl optionally substituted in the aryl radical,optionally substituted heteroaryl and heteroaryl-(C₁-C₄)-alkyloptionally substituted in the heteroaryl radical;

E is R¹⁰CO;

R is hydrogen or (C₁-C₄)-alkyl;

R⁰ is (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl optionally substituted in the arylradical or heteroaryl-(C₁-C₄)-alkyl optionally substituted in theheteroaryl radical;

R¹ is an optionally substituted radical selected from the groupconsisting of phenyl, furyl, thienyl, pyrrolyl, imidazolyl and pyridyl;

R² is hydrogen or (C₁-C₄)-alkyl;

R³ is an unsubstituted phenyl radical or naphthyl radical or a phenylradical or naphthyl radical which is substituted by one, two or threeidentical or different radicals selected from the group consisting of(C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, hydroxyl, halogen, trifluoromethyl,nitro, methylenedioxy, ethylenedioxy, hydroxycarbonyl,(C₁-C₄)-alkoxycarbonyl, aminocarbonyl, cyano, phenyl, phenoxy, benzyland benzyloxy, or R³ is pyridyl, (C₁-C₄)-alkyl, (C₂-C₄)-alkenyl,(C₂-C₄)-alkynyl, (C₅-C₆)-cycloalkyl, R¹¹NH, CON(CH₃)R⁴, CONHR⁴,CON(CH₃)R¹⁵ or CONHR¹⁵;

R⁴ is (C₁-C₈)-alkyl which is substituted by one or two identical ordifferent radicals selected from the group consisting of hydroxyl,(C₁-C₈)-alkoxy, R⁵, optionally substituted (C₃-C₈)-cycloalkyl,hydroxycarbonyl, aminocarbonyl, (C₆-C₁₀)-aryl-(C₁-C₄)-alkoxycarbonylwhich can also be substituted in the aryl radical,(C₁-C₆)-alkoxycarbonyl, Het-CO, R⁶—CO, tetrazolyl and trifluoromethyl;

R⁵ is optionally substituted (C₆-C₁₀)-aryl, (C₆-C₁₀)-aryl-(C₁-C₄)-alkyloptionally substituted in the aryl radical or an optionally substitutedmonocyclic or bicyclic 5-membered to 10-membered heterocyclic ring whichcan be aromatic, partially hydrogenated or completely hydrogenated andwhich can contain one, two or three identical or different heteroatomsselected from the group consisting of nitrogen, oxygen and sulfur;

R¹⁰ is hydroxyl, (C₁-C₈)-alkoxy, (C₆-C₁₀)-aryl-(C₁-C₄)-alkoxy which canalso be substituted in the aryl radical, optionally substituted(C₆-C₁₀)-aryloxy, (C₁-C₈)-alkylcarbonyloxy-(C₁-C₄)-alkoxy,(C₆-C₁₀)-arylcarbonyloxy-(C₁-C₄)-alkoxy, amino or mono- ordi-((C₁-C₈)-alkyl)-amino;

R¹¹ is R^(12a), R^(12a)—CO, R^(12a)—O—CO, R^(12b)—CO or R^(12a)—S(O)₂;

R^(12a) is (C₁-C₁₀)-alkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl,(C₃-C₁₂)-cycloalkyl, (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, optionallysubstituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionallysubstituted in the aryl radical, optionally substituted heteroaryl,heteroaryl-(C₁-C₈)-alkyl optionally substituted in the heteroarylradical, or the radical R¹⁵;

R^(12b) is amino, di-((C₁-C₁₀)-alkyl)-amino or R^(12a)—NH;

R¹³ is hydrogen or (C₁-C₄)-alkyl;

R¹⁵ is R¹⁶—(C₁-C₃)-alkyl or R¹⁶;

R¹⁶ is a 7-membered to 12-membered bicyclic or tricyclic radical whichis saturated and which can also contain one or two identical ordifferent heteroatoms selected from the group consisting of nitrogen,oxygen and sulfur and which can also be substituted by one or moreidentical or different substituents from the group consisting of(C₁-C₄)-alkyl and oxo;

Het is the radical of a 5-membered to 7-membered, saturated monocyclicheterocycle bonded via a ring nitrogen atom, which can contain one ortwo identical or different additional ring heteroatoms selected from thegroup consisting of oxygen, nitrogen and sulfur and which can beoptionally substituted on carbon atoms and on additional ring nitrogenatoms, where substituents on additional ring nitrogen atoms can beidentical or different radicals from the group consisting of hydrogen,R^(h), HCO, R^(h)CO or R^(h)O—CO and R^(h) is (C₁-C₆)-alkyl,(C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkyl-(C₁-C₄)-alkyl, optionallysubstituted (C₆-C₁₀)-aryl or (C₆-C₁₀)-aryl-(C₁-C₄)-alkyl optionallysubstituted in the aryl radical;

e and h independently of one another are 0 or 1;

in all their stereoisomeric forms and mixtures thereof in all ratios,and their physiologically tolerable salts.

Especially preferred compounds of the formula I are on the one handthose in which B is unsubstituted methylene or methylene which issubstituted by a (C₁-C₈)-alkyl radical, in all their stereoisomericforms and mixtures thereof in all ratios, and their physiologicallytolerable salts. Particularly especially preferred compounds of theformula I are those in which B is methylene which is substituted by a(C₁-C₈)-alkyl radical, in all their stereoisomeric forms and mixturesthereof in all ratios, and their physiologically tolerable salts.

Especially preferred compounds of the formula I are on the other handthose in which R¹ is a radical selected from the group of phenyl, furyl,thienyl, pyrrolyl, imidazolyl and pyridyl, which is unsubstituted orsubstituted by one, two or three identical or different substituentsselected from the group consisting of (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy,halogen, amino, trifluoromethyl, hydroxyl, hydroxy-(C₁-C₄)-alkyl,methylenedioxy, ethylenedioxy, phenyl, phenoxy, benzyl and benzyloxy, inall their stereoisomeric forms and mixtures thereof in all ratios, andtheir physiologically tolerable salts.

Particularly especially preferred compounds of the formula I are thosein which R¹ is a radical selected from the group of phenyl, 2-furyl,3-furyl, 2-thienyl, 3-thienyl, 3-pyrrolyl, 4-imidazolyl and 3-pyridyland 4-pyridyl, where the phenyl radical is unsubstituted or substitutedby one or two identical or different radicals selected from the groupconsisting of (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, halogen, trifluoromethyl,hydroxyl, hydroxy-(C₁-C₄)-alkyl, methylenedioxy, ethylenedioxy, phenyl,phenoxy, benzyl and benzyloxy and where the heteroaromatic radicals areunsubstituted or are substituted by one or two identical or differentradicals selected from the group of (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy,halogen, amino, trifluoromethyl, hydroxyl, hydroxy-(C₁-C₄)-alkyl,methylenedioxy, ethylenedioxy, phenyl, phenoxy, benzyl and benzyloxy, inall their stereoisomeric forms and mixtures thereof in all ratios, andtheir physiologically tolerable salts.

Very particularly especially preferred compounds of the formula I arethose in which R¹ is an unsubstituted radical selected from the group ofphenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 3-pyrrolyl,4-imidazolyl, 3-pyridyl and 4-pyridyl, in all their stereoisomeric formsand mixtures thereof in all ratios, and their physiologically tolerablesalts.

Even more especially preferred compounds of the formula I are those inwhich R¹ is an unsubstituted radical selected from the group of phenyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 4-imidazolyl and 4-pyridyl, inall their stereoisomeric forms and mixtures thereof in all ratios, andtheir physiologically tolerable salts.

Generally, compounds of the formula I are preferred which have a uniformconfiguration at chiral centers, for example on the chiral carbon atomcarrying the radicals R² and R³ when this atom is appropriatelysubstituted, and/or on the center W in the imidazolidine ring in theformula I.

The compounds of the formula I can be prepared as desired, for example,by fragment condensation of a compound of the formula II

with a compound of the formula III,

where, in the formulae II and III, the groups W, Z, B, E, R, R⁰, R² andR³ as well as e and h are defined as indicated above or alternatively inthese groups functional groups can be present in protected form or inthe form of precursors, and where G is hydroxycarbonyl,(C₁-C₆)-alkoxycarbonyl or activated carboxylic acid derivatives such asacid chlorides or active esters. If compounds of the formula I are to beprepared in which, for example, R³ in the formula I is a carboxylic acidderivative or contains such a derivative, it is also possible that inthe compounds of the formula III the radical R³ initially is ahydroxycarbonyl group present in protected form or contains such a groupin protected form, and that then the desired final group R³ issynthesized in one or more further steps only after the condensation ofthe compounds of the formulae II and III.

For the condensation of the compounds of the formula II with those ofthe formula II, the coupling methods of peptide chemistry well-known perse to the person skilled in the art are advantageously used (see, forexample, Houben-Weyl, Methoden der Organischen Chemie [Methods ofOrganic Chemistry], Volume 15/1 and 15/2, Georg Thieme Verlag,Stuttgart, 1974), incorporated herein by reference. Possible condensingagents are, for example, carbonyldiimidazole, carbodiimides such asdicyclohexylcarbodiimide or diisopropylcarbodiimide,O-((cyano(ethoxycarbonyl)methylen)amino)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TOTU) or propylphosphonic anhydride (PPA). Generally,it is necessary in the condensation to protect nonreacting amino groupspresent by reversible protective groups. The same applies to carboxylgroups not involved in the reaction, which are preferably present duringthe condensation as (C₁-C₆)-alkyl esters, for example tert-butyl esters,or as benzyl esters. Amino group protection is unnecessary if the aminogroups are still present in the form of precursors, for example as nitrogroups, and are only formed after coupling, for example byhydrogenation. After coupling, the protective groups present are removedin a suitable manner. For example, NO₂ groups (guanidino protection inamino acids), benzyloxycarbonyl groups and benzyl groups in benzylesters can be removed by hydrogenation. The protective groups of thetert-butyl type are removed under acidic conditions, while the9-fluorenylmethyloxycarbonyl radical is removed by secondary amines. Thecompounds of the formula I can also be prepared, for example, bysynthesizing the compounds stepwise on a solid phase according tocustomary methods, where the individual structural elements of themolecule can be introduced in varying sequences.

Compounds of the formula 11 in which W is R¹—A—C(R¹³) and Z is oxygencan be prepared, for example, by first reacting compounds of the formula

in a Bucherer reaction to give compounds of the formula V

in which, as well as in the formula IV, R¹, R¹³ and A are defined asindicated above (H. T. Bucherer, V. A. Lieb, J. Prakt. Chem. 141(1934),5).

Compounds of the formula VI

in which R¹, R¹³, A, B and G are defined as indicated above, can then beobtained by first reacting the compounds of the formula V, for example,with an alkylating reagent which introduces the radical —B—G into themolecule. The reaction of compounds of the formula VI with a secondreagent of the formula R⁰—LG, in which R⁰ has the meanings indicatedabove and LG is a nucleophilically substitutable leaving group, forexample halogen, in particular chlorine or bromine, (C₁-C₄)-alkoxy,optionally substituted phenoxy or a heterocyclic leaving group such as,for example, imidazolyl, leads to the corresponding compounds of theformula II. These reactions can be carried out analogously to knownmethods familiar to the person skilled in the art. Depending on theindividual case, it may be appropriate here, as in all steps in thesynthesis of the compounds of the formula I, to temporarily blockfunctional groups which could lead to secondary reactions or undesiredreactions by means of a protective group strategy tailored to thesynthesis problem, as is known to the person skilled in the art. Withrespect to the preparation of the compounds of the formulae V and VI inracemic form and in enantiomerically pure form, reference is inparticular made here to the corresponding embodiments in WO-A-96/33976,which is hereby incorporated by reference in its entirety.

If W is R¹—A—CH═C, this structural element can be introduced, forexample, by condensing, analogously to known methods, an aldehyde with adioxoimidazolidine or thioxo-oxoimidazolidine which contains anunsubstituted methylene group in the position corresponding to the groupW.

The amino compounds of the formula III can be synthesized, according toor analogously to well-known standard procedures, from startingcompounds which are commercially available or are obtainable accordingto or analogously to literature procedures.

Compounds of the formula I in which W is R¹—A—C(R¹³) can also beobtained as follows:

By reaction of α-amino acids or N-substituted α-amino acids obtainableaccording to standard procedures or preferably their esters, for examplethe methyl ester, ethyl ester, tert-butyl ester or benzyl ester, forexample of a compound of the formula VII

in which R⁰, R¹, R¹³ and A are defined as indicated above, with anisocyanate or isothiocyanate, for example of the formula VIII

in which B, E, R, R², R³, e and h are defined as indicated above and Uis isocyanato or isothiocyanato, urea derivatives or thioureaderivatives of the formula IX

are obtained for which the definitions indicated above apply, and whichare cyclized by heating with acid with hydrolysis of the ester functionsto give compounds of the formula Ia

for which the meanings indicated above apply. The cyclization of thecompounds of the formula IX to the compounds of the formula la can alsobe carried out by treatment with bases in inert solvents, for example bytreatment with sodium hydride in an aprotic solvent such asdimethylformamide. During the cyclization, functional groups can in turnbe present in protected form.

Compounds of the formula I in which W is R¹—A—C(R¹³) can also beobtained by reacting a compound of the formula VII with an isocyanate orisothiocyanate of the formula X

in which B and U are defined as indicated above for the formula VII andQ is an alkoxy group, for example a (C₁-C₄)-alkoxy group such asmethoxy, ethoxy or tert-butoxy, a (C₆-C₁₄)-aryloxy group, for examplephenoxy, or a (C₆-C₁₄)-aryl-(C₁-C₄)-alkoxy group, for example benzyloxy.In this case a compound of the formula XI

is obtained in which Z, A, B, Q, R⁰, R¹ and R¹³ are defined as indicatedabove for the formulae IX and X, which is then cyclized under theinfluence of an acid or of a base, such as described above for thecyclization of the compounds of the formula IX, to give a compound ofthe formula XII

in which W is R¹—A—C(R¹³) and Z, B, Q and R⁰ are defined as indicatedabove for the formulae Ia and X. From the compound of the formula XII acompound of the formula la is then obtained by hydrolysis of the groupCO—Q to the carboxylic acid COOH and subsequent coupling with a compoundof the formula III, as described above for the coupling of the compoundsof the formulae II and III. Here too, during the cyclization functionalgroups can be present in protected form or in the form of precursors.

A further method for the preparation of compounds of the formula Ia is,for example, the reaction of compounds of the formula XIII

in which W is R¹—A—C(R¹³) and for which otherwise the definitionsindicated above apply, with phosgene, thiophosgene or correspondingequivalents (analogously to S. Goldschmidt and M. Wick, Liebigs Ann.Chem. 575 (1952), 217-231 and C. Tropp, Chem. Ber. 61 (1928),1431-1439).

With respect to the preparation of the compounds of the formula I,reference is furthermore fully made to WO-A-95/14008, EP-A-796 855(European Patent Application 97103712.2) and the applicationscorresponding to it, as well as to WO-A-96/33976, all of which areincorpoorated by reference in their entireties.

The compounds of the formula I are valuable pharmaceutically activecompounds which are suitable, for example, for the therapy andprophylaxis of inflammatory disorders, allergic disorders or asthma. Thecompounds of the formula I and their physiologically tolerable salts canbe administered according to the invention to animals, preferably tomammals, and in particular to man, as pharmaceuticals for therapy orprophylaxis. They can be administered per se, in mixtures with oneanother or in the form of pharmaceutical preparations which permitenteral or parenteral administration and which as active constituentcontain an efficacious dose of at least one compound of the formula Iand/or its physiologically tolerable salts in addition to customarypharmaceutically innocuous excipients and/or additives.

The present invention therefore also relates to the compounds of theformula I and/or their physiologically tolerable salts for use aspharmaceuticals, the use of the compounds of the formula I and/or theirphysiologically tolerable salts for the production of pharmaceuticalsfor the therapy and prophylaxis of the diseases described above or inthe following, for example for the therapy and prophylaxis ofinflammatory disorders, and the use of the compounds of the formula Iand/or their physiologically tolerable salts in the therapy andprophylaxis of these diseases. The present invention furthermore relatesto pharmaceutical preparations which contain an efficacious dose of atleast one compound of the formula I and/or its physiologically tolerablesalts in addition to customary pharmaceutically innocuous excipientsand/or additives.

The pharmaceuticals can be administered orally, for example in the formof pills, tablets, film-coated tablets, sugar-coated tablets, granules,hard and soft gelatin capsules, solutions, syrups, emulsions orsuspensions. However, administration can also be carried out rectally,for example in the form of suppositories, or parenterally, for examplein the form of injection or infusion solutions, microcapsules or rods,or percutaneously, for example in the form of ointments, solutions ortinctures, or in another way, for example in the form of nasal sprays oraerosol mixtures.

The pharmaceutical preparations according to the invention are preparedin a manner known per se, pharmaceutically inert inorganic or organicexcipients being used in addition to the compound(s) of the formula Iand/or its/their physiologically tolerable salts. For the preparation ofpills, tablets, sugar-coated tablets and hard gelatin capsules, it ispossible to use, for example, lactose, cornstarch or derivativesthereof, talc, stearic acid or its salts etc. Excipients for softgelatin capsules and suppositories are, for example, fats, waxes,semisolid and liquid polyols, natural or hardened oils etc. Suitableexcipients for the preparation of solutions, for example injectionsolutions, or of emulsions or syrups are, for example, water, alcohols,glycerol, polyols, sucrose, invert sugar, glucose, vegetable oils etc.Suitable excipients for microcapsules, implants or rods are, forexample, copolymers of glycolic acid and lactic acid. The pharmaceuticalpreparations normally contain approximately 0.5 to 90% by weight of thecompounds of the formula I and/or their physiologically tolerable salts.

In addition to the active compounds and excipients, the pharmaceuticalpreparations can additionally contain additives, such as, for example,fillers, disintegrants, binders, lubricants, wefting agents,stabilizers, emulsifiers, preservatives, sweeteners, colorants,flavorings or aromatizers, thickeners, diluents, buffer substances, andalso solvents or solubilizers or means for achieving a depot effect, aswell as salts for altering the osmotic pressure, coating agents orantioxidants. They can also contain two or more compounds of the formulaI and/or their physiologically tolerable salts. Furthermore, they canalso contain one or more other therapeutically or prophylacticallyactive substances in addition to at least one compound of the formula Iand/or its physiologically tolerable salts, for example substanceshaving antiinflammatory action. The pharmaceutical preparations normallycontain 0.2 to 500 mg, preferably 1 to 100 mg, of active compound of theformula I and/or its physiologically tolerable salts.

The compounds of the formula I have the ability to inhibit cell—cell andcell-matrix interaction processes in which interactions between VLA-4with its ligands play a part. The efficacy of the compounds of theformula I can be demonstrated, for example, in an assay in which thebinding of cells which contain the VLA-4 receptor, for example ofleucocytes, to ligands of this receptor is measured, for example toVCAM-1, which for this purpose can advantageously also be prepared bygenetic engineering. Details of such an assay are described below. Inparticular, the compounds of the formula I are able to inhibit theadhesion and the migration of leucocytes, for example the adhesion ofleucocytes to endothelial cells which—as explained above—is controlledvia the VCAM-1/VLA-4 adhesion mechanism. Besides as antiinflammatoryagents, the compounds of the formula I and their physiologicallytolerable salts are therefore generally suitable for the therapy andprophylaxis of diseases which are based on the interaction between theVLA-4 receptor and its ligands or can be affected by an inhibition ofthis interaction, and in particular they are suitable for the therapyand prophylaxis of diseases which are caused at least partially by anundesired extent of leucocyte adhesion and/or leucocyte migration or areassociated therewith, or for whose prevention, alleviation or cure theadhesion and/or migration of leucocytes should be decreased.

The compounds of the formula I can be employed as antiinflammatories inthe case of a variety of inflammatory symptoms. They are used, forexample, for the therapy or prophylaxis of rheumatoid arthritis, ofinflammatory bowel disease (ulcerative colitis), of systemic lupuserythematosus or for the therapy or prophylaxis of inflammatorydisorders of the central nervous system such as, for example, multiplesclerosis, for the therapy or prophylaxis of asthma or of allergies, forexample allergies of the delayed type (type IV allergy). They arefurthermore suitable for the therapy or prophylaxis of cardiovasculardisorders, arteriosclerosis, of restenoses, for the therapy orprophylaxis of diabetes, for the prevention of damage to organtransplants, for the inhibition of tumor growth or formation of tumormetastases in various malignancies, for the therapy of malaria as wellas of other diseases in which blocking of the integrin VLA-4 and/orinfluencing of the leucocyte activity appears appropriate forprevention, alleviation or cure.

The dose when using the compounds of the formula I can vary within widelimits and is to be tailored to the individual conditions in eachindividual case as is customary. The dose depends, for example, on thecompound employed or on the nature and severity of the disease to betreated or on whether an acute or chronic disease state is treated orwhether prophylaxis is conducted. In general, in the case of oraladministration a daily dose of approximately 0.01 to 100 mg/kg,preferably 0.1 to 10 mg/kg, in particular 0.3 to 2 mg/kg (in each caseper kg of body weight) is appropriate in an adult weighing about 75 kgto achieve effective results. In the case of intravenous administration,the daily dose is in general approximately 0.01 to 50 mg/kg, preferably0.01 to 10 mg/kg of body weight. In particular when relatively largeamounts are administered, the daily dose can be divided into a numberof, for example 2, 3 or 4, part administrations. If appropriate,depending on individual behavior, it may be necessary to deviate upwardor downward from the indicated daily dose.

The present invention therefore also relates to the compounds of theformula I for the inhibition of the adhesion and/or migration ofleucocytes or for the inhibition of the VLA-4 receptor and the use ofthe compounds of the formula I for the production of pharmaceuticalstherefor, i.e., of pharmaceuticals for the therapy or prophylaxis ofdiseases in which leucocyte adhesion and/or leucocyte migration exhibitsan undesired extent, or of diseases in which VLA-4-dependent adhesionprocesses play a part, as well as the use of the compounds of theformula I and/or their physiologically tolerable salts in the therapyand prophylaxis of diseases of this type.

The compounds of the formula I and their salts can furthermore beemployed for diagnostic purposes, for example in in-vitro diagnoses, andas auxiliaries in biochemical investigations in which VLA-4 blocking orinfluencing of cell—cell or cell-matrix interactions is intended. Theycan furthermore be used as intermediates for the preparation of othercompounds, in particular of other pharmaceutically active compoundswhich are obtainable from the compounds of the formula I, for example,by modification or introduction of radicals or functional groups.

EXAMPLE

The following examples demonstrate the present invention. The examplesare for illustrative purposes and do not limit the scope of theinvention.

The compounds were identified by means of mass spectra (MS) and/or NMRspectra. Compounds which were purified by chromatography using an eluentwhich contained, for example, acetic acid or trifluoroacetic acid, andthen freeze-dried, sometimes still contained the acid derived from theeluent, depending on how the freeze drying was carried out, and werethus obtained partially or completely in the form of a salt of the acidused, for example in the form of the acetic acid salt or trifluoroaceticacid salt.

The abbreviations have the following meanings:

DMF N,N-dimethylformamide

THF tetrahydrofuran

DCC N,N′-dicyclohexylcarbodiimide

HOBt 1-hydroxybenzotriazole

TOTU O-(cyano(ethoxycarbonyl)methylenamino)-1,1,3,3-tetramethyluroniumtetrafluoroborate

Example 1((R,S)-2-((S)-4-Phenyl-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetyl)-L-aspartyl-L-phenylglycine

1a) tert-Butyl (R,S)-2-bromo-4-methylpentanoate (1.1)

1.96 ml of concentrated sulfuric acid and 0.515 ml of oleum (20%strength) were added to a solution of 2.5 g (12.8 mmol) of(R,S)-2-bromo-4-methylpentanoic acid in 80 ml of chloroform and 80 ml oftert-butyl acetate and the mixture was stirred at room temperature for 3h. A pH of 4 was then established by addition of 10% strength NaHCO₃solution. The aqueous phase was separated off and extracted 2× withdichloromethane. The combined organic phases were dried over sodiumsulfate. After filtration and concentration of the filtrate in vacuo,2.62 g (82%) of 1.1 were obtained.

1b) tert-Butyl(R,S)-2-((S)-4-(4-bromophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-4-methylpentanoate(1.2)

213 mg (8.87 mmol) of sodium hydride were added at 0° C. under argon toa solution of 2.08 g (7.72 mmol) of(S)-4-(4-bromophenyl)-4-methyl-2,5-dioxoimidazolidine in 20 ml ofabsolute DMF, the mixture was stirred at room temperature for 1 h, 1.94g (7.72 mmol) of 1.1 were added, and the mixture was stirred at roomtemperature for 5 h and allowed to stand at room temperature overnight.The solvent was removed in vacuo, the residue was taken up in ethylacetate and the ethyl acetate solution was washed with water. Theorganic phase was dried over sodium sulfate, the drying agent wasfiltered off and the filtrate was concentrated in vacuo. The residue waschromatographed on silica gel using heptane/ethyl acetate (2:1). Afterconcentration of the product fractions, 2.45 g (72%) of 1.2 wereobtained.

1c) tert-Butyl(R,S)-2-((S)-4-(4-bromophenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-4-methylpentanoate(1.3)

126 mg (5.24 mmol) of sodium hydride were added at 0° C. under argon toa solution of 1.92 g (4.37 mmol) of 1.2 in 10 ml of absolute DMF, themixture was stirred at room temperature for 1 h, 570 μl (4.8 mmol) ofbenzyl bromide were added and the mixture was stirred at roomtemperature for another 1 h. The solvent was removed in vacuo, theresidue was partitioned between water and ethyl acetate and, after phaseseparation, the water phase was extracted with ethyl acetate. Thecombined organic phases were dried over sodium sulfate, the drying agentwas filtered off and the filtrate was concentrated in vacuo. 2.17 g(94%) of 1.3 were obtained.

1d)(R,S)-2-((S)-4-Phenyl-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-4-methylpentanoicacid (1.4)

A solution of 1 g (1.88 mmol) of 1.3 in 100 ml of ethanol washydrogenated over 40 mg of 10% Pd/C. After 2 h, the catalyst wasfiltered off, the filtrate was concentrated in vacuo, the residue wasdissolved in ethyl acetate and the solution was washed with 10% strengthNaHCO₃ solution and water and dried over sodium sulfate. Afterfiltration and removal of the solvent in vacuo, the residue was treatedwith 10 ml of 90% strength trifluoroacetic acid. After 15 min at roomtemperature, the trifluoroacetic acid was removed in vacuo and theresidue was evaporated 2× with toluene. 740 mg (100%) of 1.4 wereobtained.

1e)((R,S)-2-((S)-4-Phenyl-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetyl)-L-aspartyl-L-phenylglycine(1.5)

166 mg (0.507 mmol) of TOTU and 172 μl (1.014 mmol) ofdiisopropylethylamine were added to a solution of 200 mg (0.507 mmol) of1.4 and 210 mg (0.507 mmol) of H-Asp(O^(t)Bu)-Phg-O^(t)Bu hydrochloridein 10 ml of absolute DMF. After stirring at room temperature for 2 h,the reaction mixture was concentrated in vacuo, the residue was taken upin ethyl acetate and the organic phase was washed 2× with saturatedNaHCO₃ solution and water. After drying over sodium sulfate, filtrationand concentration of the filtrate in vacuo, 393 mg of crude product wereobtained, which was chromatographed on silica gel using heptane/ethylacetate (3:1). After concentration of the product fractions, the residuewas dissolved in 5 ml of 90% strength trifluoroacetic acid, thetrifluoroacetic acid was removed in vacuo after 15 min at roomtemperature and the residue was dissolved in 20% strength acetic acidand freeze-dried. 219 mg (67%) of 1.5 were obtained. ES(+)-MS: 643.3(M+H)⁺

Example 2(S)-3-((R,S)-2-((S)-4-Phenyl-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-2-benzyloxycarbonylaminopropionicacid

The compound was prepared by reaction of(R,S)-2-((S)-4-phenyl-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-4-methylpentanoicacid (1.4) and tert-butyl (S)-3-amino-2-benzyloxycarbonylaminopropionateanalogously to the preparation of 1.4. After cleavage of the tert-butylester and removal of the trifluoroacetic acid in vacuo, the residue waschromatographed on silica gel using dichloromethane/methanol/aceticacid/water (9:1:0.1:0.1). ES(+)-MS: 615.4 (M+H)⁺

The tert-butyl (S)-3-amino-2-benzyloxycarbonylaminopropionate wasprepared as follows. 10 g (42 mmol) of(S)-3-amino-2-benzyloxycarbonylaminopropionic acid were shaken in amixture of 100 ml of dioxane, 100 ml of isobutylene and 8 ml of conc.H₂SO₄ in an autoclave under an N₂ pressure of 20 atm for 3 days. Excessisobutylene was blown out and 150 ml of diethyl ether and 150 ml ofsaturated NaHCO₃ solution were added to the remaining solution. Thephases were separated and the aqueous phase was extracted 2× using 100ml of diethyl ether each time. The combined organic phases were washedwith 2×100 ml of water and dried over Na₂SO₄. After removal of thesolvent in vacuo, 9.58 g (78%) of tert-butyl(S)-3-amino-2-benzyloxycarbonylaminopropionate were obtained as a paleyellow oil.

Example 3(R,S)-3-((R,S)-2-((S)-4-Phenyl-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-methylenedioxyphenyl)propionicacid

The compound was prepared by reaction of 1.4 with tert-butyl(R,S)-3-amino-3-(3,4-methylenedioxyphenyl)propionate hydrochloride andsubsequent cleavage of the tert-butyl ester as described in Example 1.ES(+)-MS: 586.3 (M+H)⁺

The tert-butyl (R,S)-3-amino-3-(3,4-methylendioxyphenyl)propionatehydrochloride was prepared by initially preparing the correspondingβ-amino acid analogously to W. M. Radionow, E. A. Postovskaya, J. Am.Chem. Soc. 1929, 51, 841 (see also Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Volume XI/2, Georg ThiemeVerlag, Stuttgart, 1958, p. 497). This was converted into thebenzyloxycarbonylamino derivative, from which the tert-butyl ester wasthen obtained according to the following synthesis procedure: 1.5 mmolof oxalyl chloride were added to 1 mmol of the 3-benzyloxycarbonylaminocarboxylic acid in 13 ml of absolute dichloromethane. After stirring atroom temperature for 4 h, the reaction mixture was concentrated and 6.5ml of tert-butanol were added to the residue. The reaction mixture wasstirred at room temperature for 1 h and concentrated in vacuo. Theresidue was taken up in ethyl acetate and extracted 2× with saturatedNaHCO₃ solution and water. The organic phase was dried over sodiumsulfate and after filtration the solvent was removed in vacuo. For thepreparation of the β-amino acid tert-butyl ester hydrochloride, thebenzyloxycarbonyl group was then removed by hydrogenation over 10% Pd/Cin methanol/HCl.

Example 4(S)-3-((R,S)-2-((R,S)-4-Phenyl-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-isopropylacetylamino)-2-(1-adamantylmethyloxycarbonylamino)propionicacid

The compound was prepared by reaction of(R,S)-2-((R,S)-3-benzyl-4-phenyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-isopropylaceticacid (prepared analogously to the procedures in Example 1 from(R,S)-4-methyl-4-phenyl-2,5-dioxoimidazolidine) with tert-butyl(S)-3-amino-2-(1-adamantylmethyloxycarbonylamino)propionate andsubsequent cleavage of the tert-butyl ester as described in Example 1.The crude product was purified on RP-18 by means of preparative HPLC.ES(+)-MS: 659.4 (M+H)⁺

The tert-butyl(S)-3-amino-2-(1-adamantylmethyloxycarbonylamino)propionate was preparedas follows.

8.9 g (40.8 mmol) of di-tert-butyl dicarbonate and subsequently, inportions, 1 N NaOH were added to a solution of 10 g (34 mmol) oftert-butyl (S)-3-amino-2-benzyloxycarbonylaminopropionate (see Example2) in 600 ml of THF/water (2:1) at 0° C. such that the pH of thesolution was between 9 and 10 (consumption of 1 N NaOH: 32 ml). Afterstirring at room temperature for 3 h, 1 l of water was added and themixture was extracted 3 times with diethyl ether. After drying theorganic phase over sodium sulfate, filtration and removal of the solventin vacuo, the residue was chromatographed on silica gel usingdichloromethane/methanol (20:1). 13.19 g (98%) of tert-butyl(S)-2-benzyloxycarbonylamino-3-tert-butoxycarbonylaminopropionate wereobtained.

13.1 g of tert-butyl(S)-2-benzyloxycarbonylamino-3-tert-butoxycarbonylaminopropionate werehydrogenated over 10% Pd/C in methanol/HCl. After 1.5 h, the mixture wasfiltered and the filtrate was concentrated in vacuo. 9.77 g (99%) oftert-butyl (S)-2-amino-3-tert-butoxycarbonylaminopropionatehydrochloride were obtained as a colorless solid.

A solution of 10.9 g (65.4 mmol) of 1-hydroxymethyladamantane and 10.6 g(65.4 mmol) of carbonyldiimidazole in 60 ml of THF was stirred at 50° C.for 1.5 h. 9.7 g (32.7 mmol) of tert-butyl(S)-2-amino-3-tert-butoxycarbonylaminopropionate hydrochloride in 25 mlof THF and 5.6 ml (32.7 mmol) of diisopropylethylamine were added, andthe mixture was stirred at 60° C. for 4 h and allowed to stand at roomtemperature overnight. The solvent was removed in vacuo and the residuewas chromatographed on silica gel using heptane/ethyl acetate (7:3). 8.7g (59%) of tert-butyl(S)-2-(1-adamantylmethyloxycarbonylamino)-3-tert-butoxycarbonylaminopropionatewere obtained as a colorless oil.

A solution of 8.7 g (19.22 mmol) of tert-butyl(S)-2-(1-adamantylmethyloxycarbonylamino)-3-tert-butoxycarbonylamino-propionatein 180 ml of trifluoroacetic acid/dichloromethane (1:1) was added after1 min to 1.5 l of ice-cold NaHCO₃ solution, the mixture was extractedthree times with dichloromethane and the dichloromethane phases werethen dried over sodium sulfate. After filtration and removal of thesolvent in vacuo, 6.35 g (94%) of tert-butyl(S)-3-amino-2-(1-adamantylmethyloxycarbonylamino)propionate wereobtained as a colorless solid.

Example 5((R,S)-4-(4-Pyridyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-L-phenylglycine

5a) (R,S)-4-(4-Pyridyl)-4-methyl-2,5-dioxoimidazolidine (5.1)

36.34 g (300 mmol) of 4-acetylpyridine and 259.2 g (2.694 mol) ofammonium carbonate were suspended in 400 ml of 50% strength ethanol.25.5 g (392 mmol) of potassium cyanide were added thereto. The mixturewas stirred at 50-60° C. for 5 hours, allowed to cool to roomtemperature, the pH was adjusted to 6.3 by addition of 6 N HCl and themixture was allowed to stand at room temperature overnight. It was againadjusted to a pH of 6.3 and the solvent was removed in vacuo. Theresidue was suspended several times using dichloromethane. The insolubleportions were in each case filtered off and the combined filtrates wereconcentrated in vacuo. The residue was chromatographed on silica gelusing dichloromethane/methanol. After concentration of the productfractions, 37.53 g (65%) of 5.1 were obtained.

5b)((R,S)-4-(4-Pyridyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-L-phenylglycine(5.2)

43.6 mg of TOTU and 68 μl of diisopropylethylamine were added to asolution of 50 mg (0.133 mmol) of((R,S)-4-(4-pyridyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)aceticacid hydrochloride (prepared by cleavage of tert-butyl((R,S)-4-(4-pyridyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)acetatewith 90% strength trifluoroacetic acid and subsequent conversion intothe hydrochloride, the tert-butyl((R,S)-4-(4-pyridyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)acetatebeing prepared by alkylation of 5.1 first with tert-butyl bromoacetateand then with benzyl bromide analogously to Example 1) and 55 mg (0.133mmol) of H-Asp(O^(t)Bu)-Phg-(O^(t)Bu)×HCl in 10 ml of absolute DMF.After 3 d at room temperature, the solvent was removed in vacuo, theresidue was taken up in ethyl acetate, and the solution was washed withsaturated NaHCO₃ solution, water and KHSO₄/K₂SO₄ solution and dried oversodium sulfate. After filtration, the solvent was removed in vacuo andthe residue was treated with 10 ml of 90% strength trifluoroacetic acid.After 1 h at room temperature, the trifluoroacetic acid was removed invacuo, the residue was partitioned between diethyl ether and water, theaqueous phase was freeze-dried and the residue was purified bychromatography on silica gel two times. 19.5 mg (25%) of 5.2 wereobtained. ES(+)-MS: 588.3 (M+H)⁺

Example 6((R,S)-2-((R,S)-4-(4-Pyridyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetyl)-L-aspartyl-L-phenylglycine

6a) tert-Butyl(R,S)-2-((R,S)-4-(4-pyridyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetate(6.1)

1.03 g (23.58 mmol) of sodium hydride were added with ice-cooling to asolution of 4.1 g (21.44 mmol) of(R,S)-4-(4-pyridyl)-4-methyl-2,5-dioxoimidazolidine (see Example 5) in30 ml of absolute DMF. The mixture was stirred at room temperature for15 min and 4.23 g (21.44 mmol) of tert-butyl(R,S)-2-bromo-4-methylpentanoate were then added. After stirring for 2 hand standing overnight at room temperature, the solvent was removed invacuo and the residue was chromatographed on silica gel usingdichloromethane/methanol (95:5). 1.2 g (15%) of tert-butyl(R,S)-2-((R,S)-4-(4-pyridyl)-4-methyl-2,5-dioxo-imidazolidin-1-yl)-2-(2-methylpropyl)acetatewere obtained, which was converted to 6.1 analogously to Example 1 byreaction with benzyl bromide.

6b)(R,S)-2-((R,S)-4-(4-Pyridyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)aceticacid hydrochloride (6.2)

1.4 g (3.1 mmol) of 6.1 in 30 ml of 90% strength trifluoroacetic acidwere stirred at room temperature for 1 h. The trifluoroacetic acid wasremoved in vacuo and the residue was partitioned between diethyl etherand water. The phases were separated, the organic phase was concentratedand the residue was purified on silica gel usingdichloromethane/methanol/acetic acid/water (9.5:0.5:0.05:0.05). 650 mg(47%) of 6.2 were obtained.

6c)((R,S)-2-((R,S)-4-(4-Pyridyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetyl)-L-aspartyl-L-phenylglycine

The compound was prepared analogously to Example 5 by reaction of 6.2with H-Asp(O^(t)Bu)-Phg-(O^(t)Bu)×HCl and subsequent cleavage of thetert-butyl ester. ES(+)-MS: 644.3 (M+H)⁺

Example 7((R,S)-4-Phenyl-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

The compound was prepared by reaction of((R,S)-4-(4-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)aceticacid (prepared analogously to Example 1 from(R,S)-4-phenyl-4-methyl-2,5-dioxoimidazolidine by alkylation with methylchloroacetate and then with benzyl bromide and subsequent cleavage ofthe methyl ester) with H-Asp(O^(t)Bu)-Phg-(O^(t)Bu)×HCl analogously toExample 1 and subsequent cleavage of the tert-butyl ester. ES(+)-MS:587.1 (M+H)⁺

Example 8((S)-4-(4-Hydroxymethylphenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

8a) Benzyl((S)-4-(4-cyanophenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)acetate(8.1)

7.73 g (160.8 mmol) of sodium hydride were added to a solution of 20 g(73.1 mmol) of((S)-4-(4-cyanophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetic acidin 120 ml of absolute DMF with ice-cooling. After stirring at roomtemperature for 30 min, 19 ml (160.8 mmol) of benzyl bromide were added.The reaction mixture was stirred at room temperature for 2 h, allowed tostand overnight, the solvent was removed in vacuo and the residue waschromatographed on silica gel using heptane/ethyl acetate (2:1). 11.43 g(35%) of 8.1 were obtained.

8b) Benzyl((S)-4-(4-formylphenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)acetate(8.2)

24.3 g of sodium hypophosphite×H₂O and 4.02 g of Raney nickel were addedto a solution of 6.08 g (13.42 mmol) of 8.1 in 200 ml of pyridine/aceticacid/water (2:1:1) at 0° C. and the reaction mixture was heated at 60°C. for 8 h. After cooling to room temperature and filtration, thereaction mixture was concentrated in vacuo, the residue was taken up inethyl acetate and the ethyl acetate phase was extracted 2× with water,2×with 10% strength citric acid solution, 2× with saturated NaHCO₃solution and with saturated sodium chloride solution. The organic phasewas dried over magnesium sulfate and, after filtration, the solvent wasremoved in vacuo. 4.82 g (79%) of 8.2 were obtained.

8c)((S)-4-(4-Hydroxymethylphenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)aceticacid (8.3)

20 ml of water and then, at 0° C., 22 mg (0.6 mmol) of sodiumborohydride were added to a solution of 500 mg (1.1 mmol) of 8.2 in 50ml of ethanol. After stirring at 0° C. for 40 min, the reaction mixturewas concentrated in vacuo, the residue was heated at 50° C. for 12 h in30 ml of 6 N hydrochloric acid/THF (1:1) and the reaction mixture wasallowed to stand overnight at room temperature. The mixture wasextracted with dichloromethane and the organic phase was dried oversodium sulfate. After filtration, the solvent was removed in vacuo, andthe residue was treated with water and freeze-dried. 440 mg of crude 8.3were obtained, which was employed in the next synthesis step withoutfurther purification.

8d)((S)-4-(4-Hydroxymethylphenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine(8.4)

A solution of 200 mg (0.54 mmol) of crude 8.3, 225 mg (0.54 mmol) ofH-Asp(O^(t)Bu)-Phg-(O^(t)Bu)×HCl and 178 mg (0.54 mmol) of TOTU wastreated with 185 μl (1.08 mmol) of diisopropylethylamine. After 1 h atroom temperature, the solvent was removed in vacuo, the residue wasdissolved in ethyl acetate and the ethyl acetate phase was extracted 2×in each case with KHSO₄/K₂SO₄ solution, saturated NaHCO₃ solution andsaturated sodium chloride solution. After phase separation, the organicphase was dried over sodium sulfate. After filtration, the solvent wasremoved in vacuo and the residue was purified by chromatography onsilica gel using methyl tert-butyl ether/heptane (8:2). Afterconcentration of the product fractions, the residue was dissolved in 5ml of 90% strength trifluoroacetic acid. After 1 h at room temperature,the trifluoroacetic acid was removed in vacuo and the residue waspurified by means of preparative HPLC on RP-18. 44 mg (13%) of 8.4 wereobtained after freeze-drying. ES(+)-MS: 617.2 (M+H)⁺

Example 9(S)-3-(((S)-4-(4-Hydroxymethylphenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-2-(1-adamantylmethyloxycarbonylamino)propionicacid

Preparation was carried out analogously to Example 8 by coupling 8.3 totert-butyl (S)-2-(1-adamantylmethyloxycarbonylamino)-3-aminopropionate(see Example 4) instead of H-Asp(O^(t)Bu)-Phg-(O^(t)Bu)×HCl. Aftercleavage of the tert-butyl ester using 90% strength trifluoroaceticacid, the crude product was partitioned between water anddichloromethane. The organic phase was separated off, dried over sodiumsulfate and, after filtration, the solvent was removed in vacuo. Theresidue was purified by preparative HPLC on RP-18. ES(+)-MS: 647.3(M+H)⁺

Example 10((R,S)-4-(4-Hydroxyphenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

10a) 1-(4-(Tetrahydropyran-2-yloxy)phenyl)ethanone (10.1)

13.62 g (100 mmol) of 4-hydroxyacetophenone and 10.04 ml (110 mmol) of3,4-dihydro-2H-pyran were suspended in 100 ml of anhydrous methylenechloride. At 0° C., 190 mg (1 mmol) of p-toluenesulfonic acid were addedwith stirring and the mixture was stirred at 0° C. for 3 hours. 10.04 ml(110 mmol) of 3,4-dihydro-2H-pyran were added again and the mixture wasstirred at room temperature for a further 3 hours. The batch was pouredinto 150 ml of water, the phases were separated and the organic phasewas extracted with saturated NaHCO₃ solution, saturated NaCl solutionand with water. The organic phase was dried over sodium sulfate,concentrated and, for purification, chromatographed on silica gel(70-200 μm) using methylene chloride as an eluent. 13.65 g (62%) of 10.1were obtained.

10b)(R,S)-4-Methyl-4-(4-(tetrahydropyran-2-yloxy)phenyl)-2,5-dioxoimidazolidine(10.2)

11.01 g (50 mmol) of 10.1 and 42.3 g (440 mmol) of ammonium carbonatewere suspended in 200 ml of 50% strength ethanol. 4.23 g (65 mmol) ofpotassium cyanide were added thereto. The mixture was stirred at 50 to60° C. for 5 hours. After a short time, a clear solution was formed. Themixture was allowed to stand at room temperature overnight and stirringwas then continued at 60° C. for 6 hours. Using 6 N HCl, the pH wasadjusted to 6.3 and the mixture was stirred with ice-cooling for 2 h.The precipitate was filtered off with suction, washed with water anddried over phosphorus pentoxide in a desiccator. 9.5 g (65%) of 10.2were obtained.

10c) Methyl((R,S)-4-methyl-4-(4-(tetrahydropyran-2-yloxy)phenyl)-2,5-dioxoimidazolidin-1-yl)acetate(10.3)

230 mg (10 mmol) of sodium were dissolved in 25 ml of anhydrous methanolunder argon. 2.9 g (10 mmol) of 10.2 were added. The mixture was heatedto reflux with stirring for 2 hours. 1.66 g (10 mmol) of potassiumiodide were then added and a solution of 0.975 ml (10 mmol) of methylchloroacetate in 1.1 ml of anhydrous methanol was added dropwise in thecourse of 15 minutes. The mixture was heated to reflux for 4 hours andthen allowed to stand at room temperature overnight. A further 0.195 ml(2 mmol) of methyl chloroacetate in 0.22 ml of anhydrous methanol wereadded and the batch was stirred under reflux for 4 hours. Theprecipitate was filtered off with suction and the filtrate wasconcentrated. The residue was dissolved in methylene chloride, insolublematter was filtered off and the filtrate was chromatographed on silicagel using methylene chloride/ethyl acetate (9:1). 2.56 g (71%) of 10.3were obtained.

10d) Methyl((R,S)-3-benzyl-4-methyl-4-(4-(tetrahydropyran-2-yloxy)phenyl)-2,5-dioxo-imidazolidin-1-yl)acetate (10.4)

2.53 g (7 mmol) of 10.3 were dissolved in 8.5 ml of anhydrous DMF underargon. At 15° C., 370 mg (7.7 mmol) of sodium hydride (50% strength inoil) were added. The mixture was stirred at 15° C. for 15 minutes and0.91 ml (7.7 mmol) of benzyl bromide was then added dropwise. Themixture was stirred at room temperature for 7.5 hours and allowed tostand at room temperature overnight. The clear solution was concentratedin vacuo and the residue was partitioned between ethyl acetate andwater. The organic phase was separated off and the aqueous phase waswashed again with ethyl acetate. The organic phases were combined,washed with water, dried over sodium sulfate and concentrated. Theresidue was chromatographed on silica gel using methylene chloride/ethylacetate (9.5:0.5). 1.59 g (50%) of 10.4 were obtained.

10e)((R,S)-4-(4-Hydroxyphenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)aceticacid (10.5)

1.53 g (3.5 mmol) of 10.4 were heated under reflux for 3 h with 30 ml ofconcentrated hydrochloric acid. After concentration of the solution invacuo, the residue was triturated with water, cooled overnight and thenfiltered off with suction. It was dried over phosphorus pentoxide in adesiccator and 1.22 g (98%) of 10.5 were obtained.

10f)((R,S)-4-(4-Hydroxyphenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycinedi-tert-butyl ester (10.6)

354 mg (1 mmol) of 10.5, 415 mg (1 mmol) ofH-Asp(O^(t)Bu)-Phg-O^(t)Bu×HCl and 135 mg (1 mmol) of HOBt weredissolved in 10 ml of DMF. At 0° C., 0.13 ml (I mmol) ofN-ethylmorpholine and 220 mg (1 mmol) of DCC were added. The mixture wasstirred at 0° C. for 1 hour and at room temperature for 3 hours andallowed to stand at room temperature overnight. The solid was filteredoff with suction and the filtrate was concentrated in vacuo. The residuewas dissolved in ethyl acetate and washed with NaHCO₃ solution,K₂SO₄/KHSO₄ solution and saturated sodium chloride solution. Afterdrying over sodium sulfate, the drying agent was filtered off and thefiltrate was concentrated in vacuo. The oily residue was triturated withdiethyl ether and the organic phase was concentrated. 730 mg (100%) of10.6 were obtained.

10g)((R,S)-4-(4-Hydroxyphenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine(10.7)

370 mg (0.52 mmol) of 10.6 were dissolved in 4 ml of 90% strengthtrifluoroacetic acid and allowed to stand at room temperature for 1hour. The mixture was then concentrated. The residue was triturated withdiethyl ether and filtered off with suction. 202 mg (64% ) of 10.7 wereobtained.

The aspartylphenylglycine derivatives of Examples 12 to 126 wereprepared by solid-phase synthesis according to the general procedureindicated in Example 11.

Example 11 General Procedure for the Preparation ofAspartylphenylglycine Derivatives by Solid-phase Synthesis

General

The syntheses on the polymeric support were carried out according to thesynthesis sequence which is shown in scheme 1. The radicals R⁵⁰ to R⁵⁵in scheme 1 have the meaning of the radicals which are located in thecorresponding position in the molecule in formula I, or they can containfunctional groups in protected form or in the form of precursors. R⁵⁰corresponds to the radical R. R⁵¹ corresponds to the radicals R⁴ andR¹⁵, where functional groups present in these radicals can be present inprotected form or in the form of precursors (the radical —NHR⁵¹ can thusbe, for example, the radical of an amino acid which is formally obtainedby removal of a hydrogen atom from the amino group). R⁵², together withthe CH group to which this radical is bonded, corresponds to the group B(R⁵² thus corresponds to a substituent on a methylene group representingB). R⁵³ corresponds to R¹³. R⁵⁴ corresponds to the group R¹—A, wherefunctional groups present therein can be present in protected form or inthe form of precursors. R⁵⁵ corresponds to the group R⁰.

The synthesis of intermediates on a relatively large scale was carriedout in special reaction vessels with frits inserted in the bottom of thereaction vessel; the synthesis of the compounds of the formula I wascarried out in syringes or reaction blocks (Act 496, MultiSynTech). Thesyntheses on the resin were monitored by on-bead analysis (FT-IR withATR unit and MAS-NMR) and cleavage of an analytical sample from theresin (HPLC, MS, NMR).

Preparation of the aspartic acid building block FmocAsp(OH)Oallyl

FmocAsp(OtBu)Oallyl (40 g, 88.7 mmol) was treated with 25 ml oftrifluoroacetic acid and the mixture was stirred at room temperature for30 min. The solvent was stripped off on a rotary evaporator. The residuewas dried in vacuo. FmocAsp(OH)Oallyl was obtained as a yellow oil (33.9g, 97%). ES(+)-MS: 395.2 (M+H)⁺

Linkage to the polymeric support (step A in scheme 1)

40 g of Wang polystyrene resin (1.1 mmol/g; Bachem) were preswollen atroom temperature with 20 ml of DMF for 5 min. After addition of asolution of 26.0 g (1.5 equivalents) of FmocAsp(OH)Oallyl and 34.3 g(1.5 equivalents) of 1-benzotriazolyloxytripyrrolidinophosphoniumhexafluorophosphate (PyBOP) and 9.3 ml (1.5 equivalents) ofdiisopropylethylamine in 120 ml of DMF, the mixture was shaken at 40° C.for 10 h. After reaction was complete, the solution was filtered offwith suction and the resin was washed with DMF (5×20 ml). After additionof a solution of acetic anhydride (10 ml) and diisopropylethylamine (9.3ml, 1.5 equivalents) in 40 ml of DMF, the mixture was again shaken atroom temperature for 30 min. The solution was filtered off with suctionand the resin was washed successively three times in each case with 40ml of DMF, methanol and dichloromethane. The resin was then dried invacuo. Determination of the loading according to the Fmoc method showeda loading of 0.6 mmol/g.

Removal of the allyl group on the polymeric support (step B)

The resin was preswollen at room temperature in DMF for 5 min underargon. After addition of tetrakis(triphenylphosphine)palladium andN-methylpyrrolidine (10 equivalents), the mixture was shaken at 40° C.for 6 h under argon. After reaction was complete, the solution wasfiltered off with suction and the resin was washed successively threetimes in each case with DMF, methanol, toluene and dichloromethane andthen dried.

Coupling with amino compounds on the polymeric support (step C)

The loaded resin with free carboxyl function was preswollen at roomtemperature in DMF for 5 min. After addition of a solution of HOBt (1.2equivalents), TOTU (1.2 equivalents) and diisopropylethylamine (1.2equivalents) in DMF, the mixture was shaken at room temperature for 30min. The amino compound (1.2 equivalents) was added dissolved in DMF.The suspension was shaken at room temperature until reaction wascomplete (HPLC checking). After reaction was complete, the solution wasfiltered off with suction and the resin was washed successively threetimes in each case with DMF, methanol, toluene and dichloromethane andthen dried.

Removal of the Fmoc protective group (step D)

For the removal of the Fmoc protective group, the resin was preswollenat room temperature in DMF for 5 min. After addition of a solution ofDMF/piperidine (1:1), it was shaken at room temperature for 20 min. Thesolution was filtered off with suction and the process was repeated. Theremoval of an analytical sample showed complete reaction according toHPLC/MS investigation. After reaction was complete, the resin was washedthree times with dichloromethane and employed directly in the coupling.

Coupling to α-halocarboxylic acids (step E)

a) Coupling with DIC

The symmetrical anhydrides were formed from α-halocarboxylic acids (5equivalents) by reaction with diisopropylcarbodiimide (2.4 equivalents)in dichloromethane for 30 minutes. After this time, 2 equivalents ofdiisopropylethylamine were added. The mixture was added to the resin andshaken at room temperature for 12 h. After reaction was complete, thesolution was filtered off with suction and the resin was washedsuccessively three times in each case with DMF, toluene anddichloromethane and then immediately reacted further.

b) Coupling with acid halides

The resin was preswollen at room temperature with dichloromethane for 5min. The α-halocarboxylic acid halides (1.5 equivalents) were addeddissolved in dichloromethane. After addition of a catalytic amount of4-dimethylaminopyridine and diisopropylethylamine (1 equivalent), themixture was shaken at room temperature for 8 h. After reaction wascomplete, the solution was filtered off with suction and the resin waswashed successively three times in each case with DMF, toluene anddichloromethane and then immediately reacted further.

Coupling of the α-haloacyl compounds to hydantoins (step F)

The 4,4-disubstituted hydantoins (2 equivalents) were activated at roomtemperature with diazabicycloundecene (DBU) (2 equivalents) in DMF. Theactivated solution was added after 15 min to the resin preswollen in DMFfor 5 min. The mixture was shaken at room temperature for 8 h. Afterreaction was complete, the solution was filtered off with suction andthe resin was washed successively three times in each case with DMF,methanol, toluene and dichloromethane and then dried.

N-Alkylation of the hydantoin on the polymeric support (step G)

a) Alkylation with cesium carbonate

The resin was preswollen at room temperature in DMF for 5 min. Afteraddition of cesium carbonate (3 equivalents), it was shaken at roomtemperature for 30 min. After addition of the alkylating agent (bromideor iodide), it was shaken at 50° C. for 6 h. After reaction wascomplete, the solution was filtered off with suction and the resin waswashed successively three times in each case with DMF,methanol/water/DMF (1.5:1.5:7), DMF, toluene and dichloromethane andthen dried.

b) Alkylation with phosphazenes

The resin was preswollen at room temperature in DMF for 5 min. Afteraddition of N′″-tert-butyl-N,N,N′,N′,N″,N″-hexamethylphosphorimidictriamide (phosphazene base P1-t-Bu) (3 equivalents), it was shaken atroom temperature for 30 min. After addition of the alkylating agent(bromide or iodide), it was shaken at room temperature for 4 h. Afterreaction was complete, the solution was filtered off with suction andthe resin was washed successively three times in each case with DMF,toluene and dichloromethane and then dried.

Removal from the resin (step H)

For the removal of the compound from the resin, a mixture oftrifluoroacetic acid/dichloromethane (1:1) was added to the resin. Thesuspension was shaken for 1 h. The resin was filtered off. The remainingsolution was concentrated in vacuo. The residue was purified by silicagel chromatography (dichloromethane and ethyl acetate).

The compounds of Examples 12 to 126, which have the structure indicatedin the formula Ib, were prepared according to the general methoddescribed in Example 11. The meanings of the radicals in the individualcompounds are indicated in Tables 1 and 2.

In Tables 1 and 2, the abbreviations have the following meanings:

Bn = Benzyl 3-BrBn = 3-Bromobenzyl 4-BrBn = 4-Bromobenzyl 4-ClBn =4-Chlorobenzyl 4-Bip = 4-Biphenylylmethyl 2-Py = 2-Pyridylmethyl 3-Py =3-Pyridylmethyl 4-Py = 4-Pyridylmethyl H = Hydrogen Me = Methyl Et =Ethyl nPr = n-Propyl iPr = Isopropyl nBu = n-Butyl iBu = Isobutyl nPe =n-Pentyl nHe = n-Hexyl All = Allyl Ph = Phenyl

The following abbreviations represent radicals which represent the group—NH—R⁵¹ in the formula Ib. They are radicals of amino acids orderivatives thereof which are formally obtained by abstraction of ahydrogen atom from the amino group of the amino acid.

TABLE 1 Ex- am- ES(+)- ple R⁵⁰ —NH-R⁵¹ R⁵² R⁵³ R⁵⁴ R⁵⁵ MS 12 Me Val BnMe Ph Bn 659 13 Me Val iPr Me Ph 4-Bip 686 14 Me Val H Me Ph Bn 568 15 HPhg H Me Ph 2-Py 589 16 H Phg H Me Ph 3-Py 589 17 H Phg H Me Ph 4-Py 58918 H Phg Et Me Ph Bn 617 19 H Phg H Ph Ph Bn 651 20 H Phg nBu Me Ph Bn644 21 H Phg iBu Me Ph Bn 644 22 H Phg nBu Me Ph 2-Py 645 23 H Phg nBuMe Ph 3-Py 645 24 H Phg nBu Me Ph 4-Py 645 25 H Phg iBu Me Ph 2-Py 64526 H Phg iBu Me Ph 3-Py 645 27 H Phg iBu Me Ph 4-Py 645 28 H Ile H Me Ph4-BrBn 647 29 H Ile Bn Me Ph Bn 659 30 H Ile iPr Me Ph Bn 610 31 H IleiPr Me Ph 4-Bip 686 32 H Ile H Me Ph Bn 568 33 H Ile nPe Me Ph Bn 639 34H Ile nPe Me Ph 4-Bip 715 35 H Ala Bn Me Ph Bn 616 36 H Ala iPr Me Ph Bn568 37 H Ala iPr Me Ph 4-Bip 644 38 H Ala H Me Ph Bn 525 39 H Ala nPe MePh Bn 596 40 H Ala nPe Me Ph 4-Bip 672 41 H Phg Bn Me Ph Bn 679 42 H PhgiPr Me Ph Bn 630 43 H Phg iPr Me Ph 4-Bip 707 44 H Phg H Me Ph Bn 588 45H Phg nPe Me Ph Bn 658 46 H Phg nPe Me Ph 4-Bip 735 47 H Phg Et Me Ph2-Py 618 48 H Phg Et Me Ph 3-Py 618 49 H Phg Et Me Ph 4-Py 618 50 H PhgH Ph Ph 2-Py 651 51 H Phg H Ph Ph 3-Py 651 52 H Phg H Ph Ph 4-Py 651 53Me Val nPe Me Ph Bn 638 54 Me Val nPe Me Ph 4-Bip 715 55 H Val H Me PhBn 554 56 H Val Bn Me Ph Bn 644 57 H Val iPr Me Ph 4-Bip 672 58 H ValiPr Me Ph Bn 596 59 H Val nPe Me Ph Bn 624 60 H Val nPe Me Ph 4-Bip 70161 H PheMor H Me Ph Bn 671 62 H PheMor Bn Me Ph Bn 762 63 H PheMor iPrMe Ph 4-Bip 790 64 H PheMor iPr Me Ph Bn 714 65 H PheMor nPe Me Ph Bn742 66 H PheMor nPe Me Ph 4-Bip 818 67 H PhePip H Me Ph Bn 670 68 HPhePip Bn Me Ph Bn 760 69 H PhePip iPr Me Ph 4-Bip 788 70 H PhePip nBuMe Ph Bn 712 71 H PhePip nPe Me Ph Bn 726 72 H PhePip pBu Me Ph 4-Bip802 73 H PhgMor H Me Ph Bn 658 74 H PhgMor Bn Me Ph Bn 748 75 H PhgMoriPr Me Ph Bn 700 76 H PhgMor nPe Me Ph Bn 728 77 H PhgMor nPe Me Ph4-Bip 804 78 H PhgPip H Me Ph Bn 656 79 H PhgPip Bn Me Ph Bn 746 80 HPhgPip iPr Me Ph 4-Bip 774 81 H PhgPip iPr Me Ph Bn 698 82 H PhgPip nPeMe Ph Bn 726 83 H PhgPip nPe Me Ph 4-Bip 802 84 H Phg 4- Me Ph Bn 713ClBn 85 H Phg All Me Ph Bn 629 86 H Phg H Me Ph 4-BrBn 667 87 H Phg H MePh 3-BrBn 667 88 H Ph(CH₂)₃NH— nBu Me Ph Bn 628 89 H Phg nBu Me Ph nPr595 90 H Phg nBu Me Ph iBu 610 91 H Phg nBu Me Ph nHe 638 92 H Phg nPrMe Ph Bn 630 93 H Phg nHe Me Ph Bn 672 94 H Phg H Me Ph nPr 539 95 HPheMor H Me Ph nPr 622 96 H PheMor iBu Me Ph Bn 727 97 H Phg H Me Ph Et525 98 H Phg H Me Ph iBu 553 99 H Phg H Me Ph iPr 539 100 H Phg nBu MePh Bn 644 101 H CH₃(CH₂)₇NH— nBu Me Ph Bn 621 102 H Phg Et Me Ph iPr 567103 H Phg nPr Me Ph Bn 630 104 H Phg nPr Me Ph iBu 595 105 H Phg nPr MePh iPr 581

TABLE 2 In all compounds of Table 2, the radical R⁵⁰ in formula lb ishydrogen, the radical —NH-R⁵¹ is Phg (=L-phenylglycyl) and the radicalR⁵² is n-butyl. Example R⁵³ R⁵⁴ R⁵⁵ ES(+)-MS 106 Me 2-Fluorophenyl Bn661 107 Me 3-Fluorophenyl Bn 661 108 Me 4-Fluorophenyl Bn 109 Me4-Fluorobenzyl Bn 110 Me 3-Trifluoromethylphenyl Bn 111 Me3-Chlorophenyl Bn 112 Bn Bn Bn 113 Me 4-Methoxybenzyl Bn 114 MeCyclohexyl Bn 115 Me Bn Bn 116 Me 2-Thienyl Bn 117 Me3-Trifluoromethylbenzyl Bn 118 Cyclopropyl Ph Bn 119 Cyclobutyl Ph Bn120 Me 3,4,5-Trimethoxyphenyl Bn 121 Me 4-Fluorophenyl H 122 Bn Bn H 123Me 4-Methoxybenzyl H 124 Me 3-Trifluoromethylbenzyl H 125 Cyclobutyl PhH 126 Me 3,4,5-Trimethoxybenzyl H

Example 127(2-((R,S)-4-Phenyl-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-2,2-dimethylacetyl)-L-aspartyl-L-phenylglycine

The compound was prepared by solid-phase synthesis analogously to thegeneral procedure described in Example 11. ES(+)-MS: 616

The 2,3-diaminopropionic acid derivatives of Examples 129 to 168 wereprepared by solid-phase synthesis according to the general procedureindicated in Example 128.

Example 128 General Procedure for the Preparation of DiaminopropionicAcid Derivatives by Solid-phase Synthesis

General

The syntheses on the polymeric support were carried out according to thesynthesis sequence which is shown in Scheme 2. The above generalexplanations for the preparation of aspartylphenylglycine derivatives bysolid-phase synthesis apply here correspondingly.

Coupling of the α-Fmoc-β-Alloc-2,3-diaminopropionic acid to thepolymeric support (step J in Scheme 2)

A solution of 0.243 g (1.8 mmol) of HOBt, 0.590 g (1.8 mmol) of TOTU,0.25 ml (1.8 mmol) of diisopropylethylamine and 0.738 g (1.8 mmol) of(S)-α-Fmoc-β-Alloc-2,3-diaminopropionic acid in 5 ml of DMF was added to1 g of Wang polystyrene resin and the mixture was shaken at roomtemperature for 12 h. The resin was filtered off and washed 3 times with10 ml of DMF each time, once with 10 ml of toluene, once with 10 ml ofmethanol and 3 times with 10 ml of dichloromethane. Determination of theloading according to the FMOC method showed a loading of 0.9 mmol/g.

Removal of the allyloxycarbonyl group on the polymeric support (step K)

The resin was preswollen at room temperature in DMF for 5 min underargon. After addition of tetrakis(triphenylphosphine)palladium andN-methylpyrrolidine (10 equivalents), the mixture was shaken at 40° C.for 6 h under argon. After reaction was complete, the solution wasfiltered off with suction and the resin was washed successively threetimes in each case with DMF, methanol, toluene and dichloromethane andthen dried.

Coupling of the α-Fmoc-2,3-diaminopropionic acid withhydantoincarboxylic acids (Step L)

A solution of 36 mg (0.27 mmol) of HOBt, 88 mg (0.27 mmol) of TOTU, 37μl (0.27 mmol) of diisopropylethylamine and 0.27 mmol of(R,S)-3-benzyl-4-phenyl-4-methyl-2,5-dioxoimidazolidin-1-ylacetic acidin 5 ml of DMF was added to 100 mg of resin which was loaded with theα-Fmoc-2,3-diaminopropionic acid (0.9 mmol/g) and the mixture was shakenat room temperature for 12 h. The resin was filtered off and washed 3times with 10 ml of DMF each time, once with 10 ml of toluene, once with10 ml of methanol and 3 times with 10 ml of dichloromethane.

Removal of the Fmoc protective group (Step M)

For the removal of the Fmoc protective group, the resin was preswollenat room temperature in DMF for 5 min. After addition of a solution ofDMF/piperidine (1:1), it was shaken at room temperature for 20 min. Thesolution was filtered off with suction and the process was repeated. Thecleavage of an analytical sample showed complete reaction according toHPLC/MS investigation. After complete reaction, the resin was washedthree times with dichloromethane and directly employed in the next step.

Acylation of the α-amino group of the 2,3-diaminopropionic acid (Step N)

a) Preparation of carboxamides (acylation with carboxylic acids)

A solution of 36 mg (0.27 mmol) of HOBt, 88 mg (0.27 mmol) of TOTU, 37μl (0.27 mmol) of diisopropylethylamine and 0.27 mmol of thecorresponding carboxylic acid of the formula R⁶⁰—COOH in 5 ml of DMF wasadded to 100 mg of resin which was loaded with the 2,3-diaminopropionicacid building block and the mixture was shaken at room temperature for12 h. The resin was filtered off and washed 3 times with 10 ml of DMFeach time, once with 10 ml of toluene, once with 10 ml of methanol and 3times with 10 ml of dichloromethane.

b) Preparation of ureas (acylation with isocyanates)

A solution of 0.27 mmol of the corresponding isocyanate of the formulaR⁶⁰—N═C═O and of a catalytic amount (1 mg) of 4-dimethylaminopyridine in5 ml of DMF were added to 100 mg of resin which was loaded with the2,3-diaminopropionic acid building block and the mixture was shaken atroom temperature for 8 h. The resin was filtered off and washed 3 timeswith 10 ml of DMF each time, once with 10 ml of toluene, once with 10 mlof methanol and 3 times with 10 ml of dichloromethane.

c) Preparation of carbamates (acylation with carbonic acid derivatives)

The corresponding alcohol (0.27 mmol) of the formula R⁶⁰—OH was shakenat 40° C. with equivalent amounts in each case of di(N-succinimidyl)carbonate and diisopropylethylamine for 5 h. The solution was added to100 mg of resin which was loaded with the 2,3-diaminopropionic acidbuilding block and the mixture was shaken at room temperature for 8 h.The resin was filtered off and washed 3 times with 10 ml of DMF eachtime, once with 10 ml of toluene, once with 10 ml of methanol and 3times with 10 ml of dichloromethane.

Removal from the resin (Step P)

For the removal of the compound from the resin, a mixture oftrifluoroacetic acid and dichloromethane (1:1) was added to the resin.The suspension was shaken for 1 h and the resin was then filtered off.The remaining solution was concentrated in vacuo. The residue waspurified by chromatography on silica gel (dichloromethane and ethylacetate).

The 3-benzyl-4-phenyl-4-methyl-2,5-dioxoimidazolidin-1-yl-acetic acidemployed in Step L was obtained according to the following generalworking procedure for the preparation of 4,4-disubstitutedhydantoincarboxylic acids.

A solution of 288 mg of potassium cyanide in 3.8 ml of water was addedby pipette to 3.0 mmol of acetophenone and 3.0 g of ammonium carbonatein 3.8 ml of ethanol. The mixture was stirred at 55° C. for 5 h. 8 ml of6 N hydrochloric acid were then slowly metered in and the mixture wasstirred at 55° C. for a further 2 h. After addition of 6.0 ml of water,the mixture was cooled to room temperature over 2 h. The product wasfiltered off with suction, washed with water and dried in the air.

The (R,S)-4-methyl-4-phenylhydantoin was suspended in DMF (20 ml/g ofhydantoin derivative) with one equivalent of cesium carbonate and themixture was stirred at room temperature for 20 min. After addition ofone equivalent of tert-butyl bromoacetate, the mixture was stirred atroom temperature for 1 h. It was then treated with water and extractedwith ethyl acetate. The combined organic phases were dried overmagnesium sulfate, filtered and concentrated. The hydantoinacetic acidester was obtained as an oil.

The hydantoinacetic acid ester was suspended in DMF (20 ml/g ofhydantoin derivative) with one equivalent of cesium carbonate and oneequivalent of benzyl bromide. The mixture was stirred at roomtemperature for 1 h. It was then treated with water and extracted withethyl acetate. The combined organic phases were dried over magnesiumsulfate, filtered and concentrated. The residue was purified bychromatography on silica gel (hexane/ethyl acetate). The3-benzylhydantoinacetic acid ester was obtained as an oil. Thetert-butyl ester group was then cleaved to give the carboxylic acidunder standard conditions using trifluoroacetic acid.

According to the general procedure described in Example 128, thecompounds of Examples 129 to 168 which have the structure indicated inthe formula Ic were prepared. The meaning of the groups X and R⁶⁰ in theindividual compounds of the formula Ic are indicated in Table 3. If X isa direct bond, this means that the group R⁶⁰ is directly bonded to thecarbonyl group a group R⁶⁰—CO thus being present.

TABLE 3 Example -X- R⁶⁰ ES-(+)-MS 129 direct bond 3-Methylphenyl 543 130direct bond 2-Methylphenyl 543 131 direct bond 2,4-Dimethoxyphenyl 589132 direct bond 3,5-Dinitrophenyl 619 133 direct bond 4-tert-Butylphenyl585 134 direct bond 2,4,5-Trimethylphenyl 571 135 —NH— 4-Chlorophenyl579 136 —NH— 4-Isopropylphenyl 586 137 —NH— 2-Nitrophenyl 589 138 directbond 4-Chlorophenyl 564 139 direct bond 4-Methylphenyl 543 140 directbond 4-Methoxyphenyl 559 141 direct bond 4-Nitrophenyl 574 142 —NH—4-(Trifluoromethoxy)phenyl 628 143 —NH— 2-Methoxyphenyl 574 144 —NH—3,5-Bis(trifluoromethyl)phenyl 680 145 —NH— Benzyl 558 146 —O—2-Methoxyethyl 527 147 —O— Prop-2-ynyl 507 148 —O— 2,2,2-Trifluoroethyl551 149 —O— Cyclopentyl 537 150 —O— 2-Cyclohexylethyl 580 151 —O—Prop-2-enyl 510 152 —O— 2-(4-Fluorophenyl)ethyl 591 153 —O—2-(4-Nitrophenyl)ethyl 618 154 —O— 2-(3-Methoxyphenyl)ethyl 604 155 —O—Cyclopropylmethyl 523 156 —O— Isobutyl 525 157 —O— 2,2-Dimethylpropyl539 158 —O— Cyclobutylmethyl 537 159 —O— 2-Ethylbutyl 553 160 —O—Cyclopentylmethyl 551 161 —O— 2-(4-Methylphenyl)ethyl 589 162 —O—4-Benzylbenzyl 650 163 —O— 4-Nitrobenzyl 604 164 —O— 2-Phenylethyl 573165 —O— 2-(4-Methoxyphenyl)ethyl 604 166 —O— 2-(1-Naphthyl)ethyl 624 167—O— 2-(2-Naphthyl)ethyl 624 168 —O— 2-(4-tert-Butylphenyl)ethyl 630

Example 169(S)-3-((S)-2-((S)-4-Phenyl-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-methylenedioxyphenyl)propionicacid

169a) Methyl (S)-2-amino-2-(4-bromophenyl)propionate (169.1)

15 g (55.7 mmol) of (S)-4-(4-bromophenyl)-4methyl-2,5-dioxoimidazolidine were suspended in 107 ml of 3 N sodiumhydroxide solution and the suspension was heated in an autoclave at 145°C. for 2 h. It was allowed to cool to room temperature, the precipitatewas filtered off and dissolved in water, and the solution was adjustedto pH 1 using 1 N hydrochloric acid. After freeze-drying, the solid wassuspended in 150 ml of absolute methanol. The suspension was cooled to−15° C. and treated with 8.8 ml of thionyl chloride. After stirring atroom temperature for 6 h and allowing to stand overnight, a further 100ml of absolute methanol and 8.8 ml of thionyl chloride were added. Themixture was stirred at room temperature for 8 h and again allowed tostand overnight. After removal of volatile components in vacuo, theresidue was adjusted to pH 9.3 using sodium hydrogen carbonate solutionand sodium carbonate solution and then the aqueous phase was extracted2× with ethyl acetate. After drying over sodium sulfate, filtration andremoval of the solvent in vacuo, 11.4 g (79%) of 169.1 were obtained.

169b) tert-Butyl(S)-2-((S)-4-(4-bromophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetate(169.2)

4.8 g of L-leucine tert-butyl ester isocyanate (prepared from L-leucinetert-butyl ester analogously to J. S. Nowick et al., J. Org. Chem. 1996,61, 3929) were added to a solution of 5.8 g (22.5 mmol) of 169.1 in 50ml of DMF. After stirring at room temperature for 4 h, the solvent wasremoved and the residue was chromatographed on silica gel usingheptane/tert-butyl methyl ether=6/4. The fractions containing theintermediate were combined, the solvent was removed in vacuo, theresidue was dissolved again in 90 ml of absolute DMF and the solutionwas treated at 0° C. with 775 mg of a 55-65% strength sodium hydridedispersion in oil. After stirring at room temperature for 3 h, thesolvent was removed in vacuo and the residue was chromatographed onsilica gel using heptane/tert-butyl methyl ether=1/1. Afterconcentration of the product fractions, 7.8 g (79%) of 169.2 wereobtained as a colorless solid.

169c) tert-Butyl(S)-2-((S)-4-(4-bromophenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetate(169.3)

540 μl (4.4 mmol) of benzyl bromide and then, at 0° C., 140 mg of a55-65% strength sodium hydride dispersion in oil were added to asolution of 1.75 g (4 mmol) of 169.2 in 20 ml of absolute DMF and themixture was stirred at 0° C. for 15 min and at room temperature for 3 h.After allowing to stand overnight, the solvent was removed in vacuo andthe residue was chromatographed on silica gel using heptane/ethylacetate=8/2. The product fractions were combined and the solvent wasremoved in vacuo. 1.97 g (93%) of 169.3 were obtained.

1 69d) tert-Butyl(S)-2-((S)-4-phenyl-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetate(169.4)

1.9 g (3.59 mmol) of 169.3 in 190 ml of ethanol were hydrogenated over76 mg of 10% palladium/carbon for 2 h. The catalyst was filtered off,the solvent was removed in vacuo, the residue was dissolved in ethylacetate and the solution was washed with a 10% strength sodium hydrogencarbonate solution. The phases were separated and the organic phase wasdried over sodium sulfate. After filtration, 1.3 g (80%) of 169.4 wereobtained.

169e)(S)-2-((S)-4-Phenyl-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetate(169.5)

1.3 g (2.89 mmol) of 169.4 in a mixture of 10 ml of 6 N hydrochloricacid and 2 ml of tetrahydrofuran were heated under reflux for 4 h. Afterremoval of the solvent in vacuo and chromatography of the residue usingheptane/ethyl acetate=3/2, 510 mg (45%) of 169.5 were obtained.

169f)(S)-3-((S)-2-((S)-4-Phenyl-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-methylenedioxyphenyl)propionicacid

The compound was prepared analogously to Example 1 by reaction of 169.5with tert-butyl (S)-3-amino-3-(3,4-methylenedioxyphenyl)propionate(prepared analogously to S. G. Davis et al., Tetrahedron Asymmetry 1991,2, 183), cleavage of the tert-butyl ester with trifluoroacetic acid asdescribed in Example 1, and subsequent purification of the crude productby means of preparative HPLC (RP18: eluent: acetonitrile/water=50/120).ES(+)-MS: 586.4 (M+H)⁺

The following two compounds can also be prepared analogously to Example169:

(S)-3-((S)-2-((S)-4-Phenyl-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(2,4-dimethoxyphenyl)propionicacid

(by reaction of 169.5 with tert-butyl(S)-3-amino-3-(2,4-dimethoxyphenyl)propionate and subsequent cleavage ofthe tert-butyl ester with trifluoroacetic acid)

(S)-3-((S)-2-((S)-4-Phenyl-3-((4-biphenylyl)methyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-methylenedioxyphenyl)propionicacid

(by reaction of(S)-2-((S)-4-phenyl-3-((4-biphenylyl)methyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)aceticacid (obtainable by reaction of 169.2 with 4-phenylbenzyl bromideanalogously to the synthesis of 169.3 and subsequent reactionsanalogously to the preparation of 169.5) with tert-butyl(S)-3-amino-3-(3,4-methylenedioxyphenyl)propionate and subsequentcleavage of the tert-butyl ester with trifluoroacetic acid)

Example 170(S)-3-((R,S)-2-((R,S)-4-(4-Pyridyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-2-(1-adamantylmethyloxycarbonylamino)propionicacid

The compound was prepared analogously to Example 5 by reaction of 6.2(see Example 6) with tert-butyl(S)-2-(1-adamantylmethyloxycarbonylamino)-3-aminopropionate (preparationsee Example 4) and subsequent cleavage of the tert-butyl ester withtrifluoroacetic acid. ES(+)-MS: 674.5 (M+H)⁺

Example 171 General Procedure for the Preparation of2-(N-((2,5-dioxoimidazolidin-1-yl)acetyl)-N-alkylamino)propionic acids

171a) General working procedure for the preparation of N-alkylatedβ-alanine tert-butyl esters

The primary alkylamine (50 mmol) was dissolved in 80 ml of methanol (ifthe alkylamine was employed in the form of the hydrochloride, the freeamine was first liberated by the addition of potassium tert-butoxide (45mmol)). 7.25 ml of tert-butyl acrylate (50 mmol) were added and afterthorough mixing the mixture was allowed to stand at room temperature for2 days. If any solids were present they were then filtered off, and themixture was concentrated in a rotary evaporator at 60° C. andcoevaporated twice with toluene. The residue was taken up in 100 ml ofabsolute diethyl ether and filtered, and the filtrate was rapidlyconcentrated. The product resulting in this way was obtained as an oilor solid and was employed in the next reaction step without furtherpurification.

171b) General working procedure for the acylation of N-alkylatedβ-alanine tert-butyl esters with hydantoincarboxylic acids and cleavageof the β-alanine tert-butyl esters

The hydantoincarboxylic acid (0.5 mmol) (see Example 128), 114 mg ofN-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.6 mmol),70 mg of 1-hydroxybenzotriazole (0.6 mmol) and the N-alkylated β-alaninetert-butyl ester (1.0 mmol) were dissolved in 2 ml of absolute DMF andthe solution was stirred at room temperature for 8 h. The reactionmixture was taken up in 100 ml of ethyl acetate and washed three timeseach with KHSO₄ solution (10%), KHCO₃ solution and water. The ethylacetate phase was dried using MgSO₄ and concentrated to dryness. Theresidue was treated with 3 ml of trifluoroacetic acid and allowed tostand at room temperature for 1 h. The trifluoroacetic acid was removedin vacuo and the residue was coevaporated with toluene and diethylether.

Example 1722-(N-(((R,S)-4-Phenyl-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl)-N-benzylamino)propionicacid

The compound was prepared starting from benzylamine according to theprocedure in Example 171. Yield: 183 mg (73%) of colorless powder.

Example 1732-(N-(((R,S)-4-Phenyl-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl)-N-octylamino)propionicacid

The compound was prepared starting from n-octylamine according to theprocedure in Example 171. Yield: 293 mg (99%) of colorless oil.

Investigation of the biological activity

The test method used for the activity of the compounds of the formula Ion the interaction between VCAM-1 and VLA-4 is an assay which isspecific for this interaction. The cellular binding components, i.e.,the VLA-4 integrins, are supplied in their natural form as surfacemolecules on human U937 cells (ATCC CRL 1593), which belong to theleucocytes group. The specific binding components used are geneticallyengineered recombinant soluble fusion proteins, consisting of theextracytoplasmatic domain of human VCAM-1 and the constant region of ahuman immunoglobulin of the subclass IgG1.

Test method

Assay for the measurement of the adhesion of U937 cells (ATCC CRL 1593)to hVCAM-1 (1-3)-IgG

1. Preparation of human VCAM-1(1-3)-IgG and human CD4-IgG

A genetic construct for the expression of the extracellular domain ofhuman VCAM-1, associated with the genetic sequence of the heavy chain ofhuman immunoglobulin IgG1 (hinge, CH2 and CH3 regions), from Dr. BrianSeed, Massachusetts General Hospital, Boston, USA was employed (cf.Damle and Aruffo, Proc. Natl. Acad. Sci. USA 1991, 88, 6403-6407). Thesoluble fusion protein hVCAM-1 (1-3)-IgG contained the threeamino-terminal extracellular immunoglobulin-like domains of human VCAM-1(Damle and Aruffo, Proc. Natl. Acad. Sci. USA 1991, 88, 6403). CD4-IgG(Zettimeissl et al., DNA and Cell Biology 1990, 9, 347) served as afusion protein for negative controls. The recombinant proteins wereexpressed as soluble proteins after DEAE/dextran-mediated DNAtransfection in COS cells (ATCC CRL1651) according to standardprocedures (Ausubel et al., Current Protocols in Molecular Biology, JohnWiley & Sons, Inc., 1994).

2. Assay for the measurement of the adhesion of U937 cells to hVCAM-1(1-3)-IgG

2.1 96-well microtiter test plates (Nunc Maxisorb) were incubated atroom temperature for 1 hour with 100 μl/well of a goat-anti-human IgGantibody solution (10 μg/ml in 50 mM tris, pH 9.5). After removal of theantibody solution, washing was carried out once with PBS.

2.2 150 μl/well of a blocking buffer (1% BSA in PBS) was incubated onthe plates at room temperature for 0.5 hour. After removal of theblocking buffer, washing was carried out once with PBS.

2.3 100 μl per well of a cell culture supernatant of transfected COScells were incubated on the plates at room temperature for 1.5 hours.The COS cells were transfected with a plasmid which codes for the threeN-terminal immunoglobulin-like domains of VCAM-1, coupled to the Fc partof human IgG₁ (hVCAM-1 (1-3)-IgG). The content of hVCAM-1 (1-3)-IgG wasabout 0.5-1 μg/ml. After removal of the culture supernatant washing wascarried out once with PBS.

2.4 The plates were incubated at room temperature for 20 minutes with100 μl/well of Fc receptor blocking buffer (1 mg/ml of γ-globulin, 100mM NaCl, 100 μM MgCl₂, 100 μM MnCl₂, 100 μM CaCl₂, 1 mg/ml of BSA in 50mM HEPES, pH 7.5). After removal of the Fc receptor blocking bufferwashing was carried out once with PBS.

2.5 20 μl of binding buffer (100 mM NaCl, 100 μM MgCl₂, 100 μM MnCl₂,100 μM CaCl₂, 1 mg/ml of BSA in 50 mM HEPES, pH 7.5) were initiallyintroduced, and the substances to be tested were added in 10 μl ofbinding buffer and incubated for 20 minutes. The controls used wereantibodies against VCAM-1 (BBT, No. BBA6) and against VLA-4 (Immunotech,No. 0764).

2.6 U937 cells were incubated in Fc receptor blocking buffer for 20minutes and then added by pipette in a concentration of 1×10⁶/ml and inan amount of 100 μl per well (final volume 125 μl/well).

2.7 The plates were slowly immersed at an angle of 45° in stop buffer(100 mM NaCl, 100 μM MgCl₂, 100 μM MnCl₂, 100 μM CaCl₂ in 25 mM tris, pH7.5) and shaken off. The process was repeated.

2.8 50 μl/well of a dye solution (16.7 μg/ml of Hoechst Dye 33258, 4%formaldehyde, 0.5% Triton X-100 in PBS) were then incubated on theplates for 15 minutes.

2.9 The plates were shaken off and slowly immersed at an angle of 45° instop buffer (100 mM NaCl, 100 μM MgCl₂, 100 μM MnCl₂, 100 μM CaCl₂ in 25mM tris, pH 7.5). The process was repeated. Then, with the liquid,measurements were made in a cytofluorimeter (Millipore) (sensitivity: 5,filter: excitation wavelength: 360 nm, emission wavelength: 460 nm).

The intensity of the light emitted by the stained U937 cells is ameasure of the number of the U937 cells adherent to the hVCAM-1(1-3)-IgG and remaining on the plate and thus a measure of the abilityof the added test substance to inhibit this adhesion. From theinhibition of the adhesion at various concentrations of the testsubstance, the concentration IC₅₀ was calculated which leads to a 50%inhibition of adhesion.

The following test results were obtained:

U934/VCAM-1 cell adhesion test Example IC₅₀ (μM) 4 45 7 8 8 4.5 9 4 109.5

The disclosure of german application 19741235.1, filed Sep. 18, 1997(for which priority under 35 USC § 119 is claimed) is herebyincorporated by references in its entirety:

Although only certain exemplary embodiments of this invention have beendescribed in detail above, those skilled in the art will readilyappreciate that many modifications are possible in the exemplaryembodiments without materially departing from the teachings andadvantages of this invention. Accordingly, all such modifications areintended to be included within the scope of this invention.

What is claimed is:
 1. A compound of the formula I,

in which W is R¹—A—C(R¹³); Z is oxygen or sulfur; A is a direct bond or(C₁-C₂)-alkylene; B is a divalent radical selected from the groupconsisting of (C₁-C₆)-alkylene, (C₂-C₆)-alkenylene, phenylene,phenylene-(C₁-C₃)-alkyl, (C₁-C₃)-alkenylphenyl, where the divalent(C₁-C₆)-alkylene radical is unsubstituted or substituted by a radicalselected from the group consisting of (C₁-C₈)-alkyl, (C₂-C₈)-alkenyl,(C₂-C₈)-alkynyl, (C₃-C₁₀)-cycloalkyl, (C₃-C₁₀)-cycloalkyl-(C₁-C₆)-alkyl,unsubstituted or substituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₆)-alkylunsubstituted or substituted in the aryl radical, unsubstituted orsubstituted heteroaryl, and heteroaryl-(C₁-C₆)-alkyl unsubstituted orsubstituted in the heteroaryl radical; E is tetrazolyl, (R⁸O)₂P(O),HOS(O)₂, R⁹NHS(O)₂ or R¹⁰CO; R is hydrogen, (C₁-C₈)-alkyl,(C₃-C₁₂)-cycloalkyl, (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, unsubstituted orsubstituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl unsubstituted orsubstituted in the aryl radical, unsubstituted or substitutedheteroaryl, or heteroaryl-(C₁-C₈)-alkyl unsubstituted or substituted inthe heteroaryl radical; R⁰ is (C₃-C₁₂)-cycloalkyl,(C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, (C₆-C₁₂)-bicycloalkyl,(C₆-C₁₂)-bicycloalkyl-(C₁-C₈)-alkyl, (C₆-C₁₂)-tricycloalkyl,(C₆-C₁₂)-tricycloalkyl-(C₁-C₈)-alkyl, unsubstituted or substituted(C₆-C₁₄)-aryl, C₆-C₁₄-aryl-(C₁-C₈)-alkyl unsubstituted or substituted inthe aryl radical, unsubstituted or substituted heteroaryl,heteroaryl-(C₁-C₈)-alkyl unsubstituted or substituted in the heteroarylradical, H—CO, (C₁-C₈)-alkyl-CO, (C₃-C₁₂)-cycloalkyl-CO,(C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl-CO, (C₆-C₁₂)-bicycloalkyl-CO,(C₆-C₁₂)-bicycloalkyl-(C₁-C₈)-alkyl-CO, (C₆-C₁₂)-tricycloalkyl-CO,(C₆-C₁₂)-tricycloalkyl-(C₁-C₈)-alkyl-CO, unsubstituted or substituted(C₆-C₁₄)-aryl-CO, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl-CO unsubstituted orsubstituted in the aryl radical, unsubstituted or substitutedheteroaryl-CO, heteroaryl-(C₁-C₈)-alkyl-CO unsubstituted or substitutedin the heteroaryl radical, (C₁-C₈)-alkyl-S(O)_(n),(C₃-C₁₂)-cycloalkyl-S(O)_(n),(C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl-S(O)_(n),(C₆-C₁₂)-bicycloalkyl-S(O)_(n), (C₆-C₁₂)-bicycloalkyl-(C₁-C₈)-alkyl-S(O)_(n), (C₆-C₁₂)-tricycloalkyl-S(O)_(n),(C₆-C₁₂)-tricycloalkyl-(C₁-C₈)-alkyl-S(O)_(n), unsubstituted orsubstituted (C₆-C₁₄)-aryl-S(O)_(n), (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl-S(O)_(n)unsubstituted or substituted in the aryl radical, unsubstituted orsubstituted heteroaryl-S(O)_(n) or heteroaryl-(C₁-C₈)-alkyl-S(O)_(n)unsubstituted or substituted in the heteroaryl radical, where n is 1 or2; R¹ is an unsubstituted or substituted radical selected from the groupconsisting of phenyl, furyl, thienyl, pyrrolyl, imidazolyl, and pyridyl,where each of these radicals is or is not benzo-fused; R² is hydrogen,(C₁-C₈)-alkyl, unsubstituted or substituted (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₈)-alkyl unsubstituted or substituted in the arylradical or (C₃-C₈)-cycloalkyl; R³ is hydrogen, (C₁-C₈)-alkyl,unsubstituted or substituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkylunsubstituted or substituted in the aryl radical, unsubstituted orsubstituted heteroaryl, heteroaryl-(C₁-C₈)-alkyl unsubstituted orsubstituted in the heteroaryl radical, (C₃-C₈)-cycloalkyl,(C₃-C₈)-cycloalkyl-(C₁-C₈)-alkyl, (C₆-C₁₂)-bicycloalkyl,(C₆-C₁₂)-bicycloalkyl-(C₁-C₈)-alkyl, (C₆-C₁₂)-tricycloalkyl,(C₆-C₁₂)-tricycloalkyl-(C₁-C₈)-alkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynylor R¹¹NH; R⁸ is hydrogen, (C₁-C₁₈)-alkyl, unsubstituted or substituted(C₆-C₁₄)-aryl or (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl which is unsubstituted orsubstituted in the aryl radical; R⁹ is hydrogen, aminocarbonyl,(C₁-C₁₈)-alkylaminocarbonyl, (C₃-C₈)-cycloalkylaminocarbonyl,unsubstituted or substituted (C₆-C₁₄)-arylaminocarbonyl, (C₁-C₁₈)-alkyl,unsubstituted or substituted (C₆-C₁₄)-aryl or (C₃-C₈)-cycloalkyl; R¹⁰ ishydroxyl, (C₁-C₁₈)-alkoxy, (C₆-C₁₄)-aryl-(C₁-C₈)-alkoxy which isunsubstituted or substituted in the aryl radical, unsubstituted orsubstituted (C₆-C₁₄)-aryloxy, (C₁-C₈)-alkylcarbonyloxy-(C₁-C₆)-alkoxy,(C₆-C₁₄)-arylcarbonyloxy-(C₁-C₆)-alkoxy, amino or mono- ordi((C₁-C₁₈)-alkyl)-amino; R¹¹ is hydrogen, R^(12a), R^(12a)—CO, H—CO,R^(12a)—O—CO, R^(12b)—CO, R^(12b)—CS, R^(12a)—S(O)₂ or R^(12b)—S(O)₂;R^(12a) is (C₁-C₁₈)-alkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl,(C₃-C₁₂)-cycloalkyl, (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, unsubstituted orsubstituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl unsubstituted orsubstituted in the aryl radical, unsubstituted or substitutedheteroaryl, heteroaryl-(C₁-C₈)-alkyl unsubstituted or substituted in theheteroaryl radical, or the radical R¹⁵; R^(12b) is amino,di-((C₁-C₁₈)-alkyl)-amino, or R^(12a)—NH; R¹³ is (C₁-C₆)-alkyl,unsubstituted or substituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₆)-alkylunsubstituted or substituted in the aryl radical, (C₃-C₈)-cycloalkyl, or(C₃-C₈)-cyclo-(C₁-C₆)-alkyl; R¹⁵ is R¹⁶-(C₁-C₆)-alkyl or R¹⁶; R¹⁶ is a6-membered to 24-membered bicyclic or tricyclic radical which issaturated or partially unsaturated and which contains none or one, two,three, or four identical or different additional heteroatoms selectedfrom the group consisting of nitrogen, oxygen, and sulfur and which isunsubstitueted or substitueted by one or more identical or differentsubstituents selected from the group consisting of (C₁-C₄)-alkyl andoxo; and e and h independently of one another are 0 or 1; in any of itssteroisomeric forms or mixtures thereof in any ratio, or aphysiologically tolerable salt of the compound.
 2. A compound of theformula I as claimed in claim 1, in which W is R¹—A—C(R¹³); Z is oxygenor sulfur; A is a direct bond or methylene; B is a divalent methyleneradical or ethylene radical, both of which are unsubstituted orsubstituted by a radical selected from the group consisting of(C₁-C₈)-alkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl, (C₃-C₁₀)-cycloalkyl,(C₃-C₁₀)-cycloalkyl-(C₁-C₆)-alkyl, unsubstituted or substituted(C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₆)-alkyl unsubstituted or substitutedin the aryl radical, unsubstituted or substituted heteroaryl andheteroaryl-(C₁-C₆)-alkyl unsubstituted or substituted in the heteroarylradical; E is tetrazolyl or R¹⁰CO; R is hydrogen or (C₁-C₈)-alkyl; R⁰ is(C₃-C₁₂)-cycloalkyl, (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl,(C₆-C₁₂)-bicycloalkyl, (C₆-C₁₂)-bicycloalkyl-(C₁-C₈)-alkyl,(C₆-C₁₂)-tricycloalkyl, (C₆-C₁₂)-tricycloalkyl-(C₁-C₈)-alkyl,unsubstituted or substituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkylunsubstituted or substituted in the aryl radical, unsubstituted orsubstituted heteroaryl, heteroaryl-(C₁-C₈)-alkyl unsubstituted orsubstituted in the heteroaryl radical, H—CO, (C₁-C₈)-alkyl-CO,(C₃-C₁₂)-CO, (C₃-C₁₂)-cycloalkyl- (C₁-C₈)-alkyl-CO,(C₆-C₁₂)-bicycloalkyl-CO, (C₆-C₁₂)-bicycloalkyl-(C₁-C₈)-alkyl-CO,(C₆-C₁₂)-tricycloalkyl-CO, (C₆-C₁₂)-tricycloalkyl-(C₁-C₈)-alkyl-CO,unsubstituted or substituted (C₆-C₁₄)-aryl-CO,(C₆-C₁₄)-aryl-(C₁-C₈)-alkyl-CO unsubstituted or substituted in the arylradical, unsubstituted or substituted heteroaryl-CO,heteroaryl-(C₁-C₈)-alkyl-CO unsubstituted or substituted in theheteroaryl radical, (C₁-C₈)-alkyl-S(O)_(n),(C₃-C₁₂)-cycloalkyl-S(O)_(n),(C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl-S(O)_(n),(C₆-C₁₂)-bicycloalkyl-S(O)_(n),(C₆-C₁₂)-bicycloalkyl-(C₁-C₈)-alkyl-S(O)_(n),(C₆-C₁₂)-tricycloalkyl-S(O)_(n),(C₆-C₁₂)-tricycloalkyl-(C₁-C₈)-alkyl-S(O)_(n), unsubstituted orsubstituted (C₆-C₁₄)-aryl-S(O)_(n); (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl-S(O)_(n)unsubstituted or substituted in the aryl radical, unsubstituted orsubstituted heteroaryl-S(O)_(n) or heteroaryl-(C₁-C₈)-alkyl-S(O)_(n)unsubstituted or substituted in the heteroaryl radical, where n is 1 or2; R¹ is an unsubstituted or substituted radical selected from the groupconsisting of phenyl, furyl, thienyl, pyrrolyl, imidazolyl, and pyridyl,where each of these radicals is or is not benzo-fused; R² is hydrogen or(C₁-C₈)-alkyl; R³ is hydrogen, (C₁-C₈)-alkyl, unsubstituted orsubstituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl unsubstituted orsubstituted in the aryl radical, unsubstituted or substitutedheteroaryl, heteroaryl-(C₁-C₈)-alkyl unsubstituted or substituted in theheteroaryl radical, (C₃-C₈)-cycloalkyl,(C₃-C₈)-cycloalkyl-(C₁-C₈)-alkyl, (C₆-C₁₂)-bicycloalkyl,(C₆-C₁₂)-bicycloalkyl-(C₁-C₈)-alkyl, (C₆-C₁₂)-tricycloalkyl,(C₆-C₁₂)-tricycloalkyl-(C₁-C₈)-alkyl, (C₂-C₈)-alkenyl or (C₂-C₈)-alkynylor R¹¹NH; R¹⁰ is hydroxyl, (C₁-C₁₈)-alkoxy, (C₆-C₁₄)-aryl-(C₁-C₈)-alkoxywhich is unsubstituted or substituted in the aryl radical, unsubstitutedor substituted (C₆-C₁₄)-aryloxy,(C₁-C₈)-alkylcarbonyloxy-(C₁-C₆)-alkoxy,(C₆-C₁₄)-arylcarbonyloxy-(C₁-C₆)-alkoxy, amino or mono- ordi-((C₁-C₁₈)-alkyl)-amino; R¹¹ is hydrogen, R^(12a), R^(12a)—CO,R^(12a)—O—CO, R^(12b)—CO, R^(12b)—CS or R^(12a)—S(O)₂; R^(12a) is(C₁-C₁₈)-alkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl, (C₃-C₁₂)-cycloalkyl,(C₃-C₁₂)-cycloalkyl-(C₁-C₈-alkyl, unsubstituted or substituted(C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl unsubstituted or substitutedin the aryl radical, unsubstituted or substituted heteroaryl,heteroaryl-(C₁-C₈)-alkyl unsubstituted or substituted in the heteroarylradical, or the radical R¹⁵; R^(12b) is amino, di-((C₁-C₁₈)-alkyl)-aminoor R^(12a)—NH; R¹³ is (C₁-C₆)-alkyl; R¹⁵ is R¹⁶-(C₁-C₆)-alkyl or R¹⁶;R¹⁶ is a 6-membered to 14-membered bicyclic or tricyclic radical whichis saturated or partially unsaturated and which contains none or one,two, three or four identical or different additional heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur andwhich is unsubstituted or substituted by one or more identical ordifferent substituents selected from the group consisting of(C₁-C₄-alkyl and oxo; and e and h independently of one another are 0 or1; in any of its stereoisomeric forms or mixtures thereof in any ratio,or a physiologically tolerable salt of the compound.
 3. A compound ofthe formula I as claimed in claim 1, in which W is R¹—A—C(R¹³); Z isoxygen; A is a direct bond or methylene; B is a divalent methyleneradical or ethylene radical, both of which are unsubstituted orsubstituted by a radical selected from the group consisting of(C₁-C₈)-alkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl, (C₃-C₁₀)-cycloalkyl,(C₃-C₁₀)-cycloalkyl-(C₁-C₆)-alkyl, unsubstituted or substituted(C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₆)-alkyl, unsubstituted or substitutedin the aryl radical, unsubstituted or substituted heteroaryl andheteroaryl-(C₁-C₆)-alkyl unsubstituted or substituted in the heteroarylradical; E is R¹⁰CO; R is hydrogen or (C₁-C₄)-alkyl; R⁰ is(C₃-C₁₂)-cycloalkyl, (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl,(C₆-C₁₂)-bicycloalkyl, (C₆-C₁₂)-bicycloalkyl-(C₁-C₈)-alkyl,(C₆-C₁₂)-tricycloalkyl, (C₆-C₁₂)-tricycloalkyl-(C₁-C₈)-alkyl,unsubstituted or substituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkylunsubstituted or substituted in the aryl radical, unsubstituted orsubstituted heteroaryl or heteroaryl-(C₁-C₈)-alkyl unsubstituted orsubstituted in the heteroaryl radical; R¹ is an unsubstituted orsubstituted radical selected from the group consisting of phenyl, furyl,thienyl, pyrrolyl, imidazolyl, and pyridyl; R² is hydrogen or(C₁-C₄)-alkyl; R³ is (C₁-C₈)-alkyl, unsubstituted or substituted(C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl unsubstituted or substitutedin the aryl radical, unsubstituted or substituted heteroaryl,heteroaryl-(C₁-C₄)-alkyl unsubstituted or substituted in the heteroarylradical, (C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkyl-(C₁-C₄)-alkyl,(C₆-C₁₂)-bicycloalkyl, (C₆-C₁₂)-bicycloalkyl-(C₁-C₄)-alkyl,(C₆-C₁₂)-tricycloalkyl, (C₆-C₁₂)-tricycloalkyl-(C₁-C₄)-alkyl or R¹¹NH;R¹⁰ is hydroxyl, (C₁-C₈)-alkoxy, (C₆-C₁₄)-aryl-(C₁-C₈)-alkoxy which isunsubstituted or substituted in the aryl radical, unsubstituted orsubstituted (C₆-C₁₄)-aryloxy, (C₁-C₈)-alkylcarbonyloxy-(C₁-C₆)-alkoxy,(C₆-C₁₄)-arylcarbonyloxy-(C₁-C₆)-alkoxy, amino or mono- or di-((C₁-C₈)-alkyl)-amino; R¹¹ is R^(12a), R^(12a)—CO, R^(12a)—O—CO,R^(12b)—CO, or R^(12a)—S(O)₂; R^(12a) is (C₁-C₁₀)-alkyl,(C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl, (C₃-C₁₂)-cycloalkyl,(C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, unsubstituted or substituted(C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl unsubstituted or substitutedin the aryl radical, unsubstituted or substituted heteroaryl,heteroaryl-(C₁-C₈)-alkyl unsubstituted or substituted in the heteroarylradical, or the radical R¹⁵; R^(12b) is amino,di-((C₁-C₁₀)-alkyl)-amino, or R^(12a)—NH; R¹³ is (C₁-C₄)-alkyl; R¹⁵ isR¹⁶-(C₁-C₃)-alkyl or R¹⁶; R¹⁶ is a 7-membered to 12-membered bicyclic ortricyclic radical which is saturated or partially unsaturated and whichcontains none or one, two identical or different additional heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur andwhich is unsubstituted or substituted by one or more identical ordifferent substituents selected from the group consisting of(C₁-C₄)-alkyl and oxo; and e and h independently of one another are 0 or1; in any of its stereoisomeric forms or mixtures thereof in any ratio,or a physiologically tolerable salt of the compound.
 4. A compound ofthe formula I as claimed in claim 1, in which W is R¹—A—C(R¹³); Z isoxygen; A is a direct bond or methylene; B is an unsubstituted methyleneradical or a methylene radical which is substituted by a radicalselected from the group consisting of (C₁-C₈)-alkyl, (C₂-C₈)-alkenyl,(C₂-C₈)-alkynyl, (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl,unsubstituted or substituted (C₆-C₁₀)-aryl, (C₆-C₁₀)-aryl-(C₁-C₄)-alkylunsubstituted or substituted in the aryl radical, unsubstituted orsubstituted heteroaryl, and heteroaryl-(C₁-C₄)-alkyl unsubstituted orsubstituted in the heteroaryl radical; E is R¹⁰CO; R is hydrogen or(C₁-C₄)-alkyl; R⁰ is (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl unsubstituted orsubstituted in the aryl radical or heteroaryl-(C₁-C₄)-alkylunsubstituted or substituted in the heteroaryl radical; R¹ is anunsubstituted or substituted radical selected from the group consistingof phenyl, furyl, thienyl, pyrrolyl, imidazolyl, and pyridyl; R² ishydrogen or (C₁-C₄)-alkyl; R³ is an unsubstituted phenyl radical ornaphthyl radical or a phenyl radical or naphthyl radical which issubstituted by one, two or three identical or different radicalsselected from the group consisting of (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy,hydroxyl, halogen, trifluoromethyl, nitro, methylenedioxy,ethylenedioxy, hydroxycarbonyl, (C₁-C₄)-alkoxycarbonyl, aminocarbonyl,cyano, phenyl, phenoxy, benzyl and benzyloxy, or R³ is pyridyl,(C₁-C₄)-alkyl, (C₂-C₄)-alkenyl, (C₂-C₄)-alkynyl, (C₅-C₆)-cycloalkyl orR¹¹NH; R¹⁰ is hydroxyl, (C₁-C₈)-alkoxy, (C₆-C₁₀)-aryl-(C₁-C₄)-alkoxywhich is unsubstituted or substituted in the aryl radical, unsubstitutedor substituted (C₆-C₁₀)-aryloxy, (C₁-C₈)-alkycarbonyloxy-(C₁-C₄)-alkoxy,(C₆-C₁₀)-arylcarbonyloxy-(C₁-C₄)-alkoxy, amino or mono- ordi-((C₁-C₈)-alkyl)-amino; R¹¹ is R^(12a), R^(12a)—CO, R^(12a)—O—CO,R^(12b)—CO, or R^(12a)—S(O)₂; R^(12a) is (C₁-C₁₀)-alkyl,(C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl, (C₃-C₁₂)-cycloalkyl,(C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, unsubstituted or substituted(C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl unsubstituted or substitutedin the aryl radical, unsubstituted or substituted heteroaryl,heteroaryl-(C₁-C₈)-alkyl unsubstituted or substituted in the heteroarylradical, or the radical R¹⁵; R^(12b) is amino, di-(C₁-C₈)-alkyl)-amino,or R^(12a)—NH; R¹³ is (C₁-C₄)-alkyl; R¹⁵ is R¹⁶-(C₁-C₃)-alkyl or R¹⁶;R¹⁶ is a 7-membered to 12-membered bicyclic or tricyclic radical whichis saturated and which contains none or one or two identical ordifferent additional heteroatoms selected from the group consisting ofnitrogen, oxygen, and sulfur and which is unsubstituted or substitutedby one or more identical or different substituents selected from thegroup consisting of (C₁-C₄)-alkyl and oxo; and e and h independently ofone another are 0 or 1; in any of its stereoisomeric forms or mixturesthereof in any ratio, or a physiologically tolerable salt of thecompound.
 5. A compound of the formula I as claimed in claim 1, in whichB is unsubstituted methylene or methylene which is substituted by a(C₁-C₈)-alkyl radical, in any of its stereoisomeric forms or mixturesthereof in any ratio, or a physiologically tolerable salt of thecompound.
 6. A compound of the formula I as claimed in claim 1, in whichR¹ is a radical selected from the group consisting of phenyl, furyl,thienyl, pyrrolyl, imidazolyl, and pyridyl, which is unsubstituted orsubstituted by one, two or three identical or different substitutentsfrom the group consisting of (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, halogen,amino, trifluoromethyl, hydroxyl, hydroxy-(C₁-C₄)-alkyl, methylenedioxy,ethylenedioxy, phenyl, phenoxy, benzyl, and benzyloxy, in any of itsstereoisomeric forms or mixtures thereof in any ratio, or aphysiologically tolerable salt of the compound.
 7. A compound of theformula I as claimed in claim 1, in which R¹ is a radical selected fromthe group consisting of phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,3-pyrrolyl, 4-imidazolyl, 3-pyridyl, and 4-pyridyl, where the phenylradical is unsubstituted or substituted by one or two identical ordifferent radicals selected from the group consisting of (C₁-C₄)-alkyl,(C₁-C₄)-alkoxy, halogen, trifluoromethyl, hydroxyl,hydroxy-(C₁-C₄)-alkyl methylenedioxy, ethylenedioxy, phenyl, phenoxy,benzyl and benzyloxy and where the heteroaromatic radicals areunsubstituted or are substituted by one or two identical or differentradicals selected from the group consisting of (C₁-C₄)-alkyl,(C₁-C₄)-alkoxy, halogen, amino, trifluoromethyl, hydroxyl,hydroxy-(C₁-C₄)-alkyl, methylenedioxy, ethylenedioxy, phenyl, phenoxy,benzyl and benzyloxy, in any of its stereoisomeric forms or mixturesthereof in any ratio, or a physiologically tolerable salt of thecompound.
 8. A compound of the formula I as claimed in claim 1, in whichR¹ is an unsubstituted radical selected from the group consisting ofphenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 3-pyrrolyl,4-imidazolyl, 3-pyridyl and 4-pyridyl, in any of its stereoisomericforms or mixtures thereof in any ratio, or a physiologically tolerablesalt thereof.
 9. A compound of the formula I as claimed in claim 1, inwhich R¹ is an unsubstituted radical selected from the group consistingof phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 4-imidazolyl and4-pyridyl, in any of its stereoisomeric forms or mixtures thereof in anyratio, or a physiologically tolerable salt of the compound.
 10. Aprocess for the preparation of a compound of the formula I as claimed inclaim 1, which comprises condensing a compound of the formula II

with a compound of the formula III,

where, in the formulae II and III, the groups W, Z, B, E, R, R⁰, R², andR³, as well as e and h are as defined in claim 1 or functional groupsare present in protected form or in the form of precursors, and where Gis hydroxycarbonyl, (C₁-C₆)-alkoxycarbonyl or an activated carboxylicacid derivative.
 11. A pharmaceutical comprising a compound of theformula I as claimed in claim 1 or a physiologically tolerable salt ofthe compound.
 12. A pharmaceutical preparation which comprises one ormore compounds of the formula I as claimed in claim 1 or aphysiologically tolerable salt of the compound and a pharmaceuticallyinnocuous excipient or additive.
 13. A method for the treatment ofinflammation, comprising administering to a mammal in need thereof acompound of the formula I claimed in claim 1 or a physiologicallytolerable salt of the compound.
 14. A method for the treatment ofrheumatoid arthritis, of inflammatory bowel disease, of systemic lupuserythematosus, or of inflammatory disorders of the central nervoussystem, comprising administering to a mammal in need thereof a compoundof formula 1 as claimed in claim 1 or a physiologically tolerable saltof the compound.
 15. A method for the treatment of asthma or allergy,comprising administering to a mammal in need thereof a compound offormula I as claimed in claim 1 or a physiologically tolerable salt ofthe compound.
 16. A method for the treatment of a cardiovasculardisorder, arteriosclerosis, of restenoses or of diabetes, of damage toan organ transplant, or of malaria, comprising administering to a mammalin need thereof a compound of formula I as claimed in claim 1 or aphysiologically tolerable salt of the compound.
 17. A method for theinhibition of the adhesion or migration of leucocytes or of the adhesionand migration of leucocytes, or for the inhibition of the VLA-4receptor, comprising administering to a mammal in need thereof acompound of formula I as claimed in claim 1 or a physiologicallytolerable salt of the compound.